6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one allosteric modulators of the M4 muscarinic acetylcholine receptor

ABSTRACT

The present invention is directed to 6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one compounds which are allosteric modulators of the M4 muscarinic acetylcholine receptor. The present invention is also directed to uses of the compounds described herein in the potential treatment or prevention of neurological and psychiatric disorders and diseases in which M4 muscarinic acetylcholine receptors are involved. The present invention is also directed to compositions comprising these compounds. The present invention is also directed to uses of these compositions in the potential prevention or treatment of such diseases in which M4 muscarinic acetylcholine receptors are involved.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of application Ser. No. 15/386,009,filed Dec. 21, 2016, which claims priority under 35 U.S.C. § 119(b) fromInternational Application No. PCT/CN15/098382, filed Dec. 23, 2015, andclaims priority under 35 U.S.C. § 119(e) from U.S. Ser. No. 62/419,630,filed Nov. 9, 2016.

BACKGROUND OF THE INVENTION

Acetylcholine (ACh) is a key neurotransmitter that modulates neuronalfunction in the peripheral nervous system (PNS) and central nervoussystem (CNS). ACh mediates its actions via two families of receptors,termed the muscarinic ACh receptors (mAChRs) and the nicotinic AChreceptors (nAChRs). A large body of evidence suggests that basalforebrain cholinergic neurons and basalo-cortical cholinergic pathwaysare selectively vulnerable to degeneration in Alzheimer's disease. Ithas therefore been hypothesized that cholinergic hypofunctioncontributes to the cognitive deficits of patients suffering fromAlzheimer's disease. Consequently, acetylcholinesterase inhibitors,which inhibit ACh hydrolysis and potentiate cholinergic signaling havebeen demonstrated to not only provide improvements in cognitive symptomsassociated with Alzheimer's disease, but also show efficacy in treatingthe psychiatric symptoms. Acetylcholinesterase inhibitors, however, havenot been shown to change the underlying disease pathology.

Another potential pharmacotherapeutic target to counteract cholinergichypofunction is the activation of muscarinic acetylcholine receptors(mAChRs). Muscarinic acetylcholine receptors are members of the Gprotein-coupled receptor superfamily which mediate the actions of theneurotransmitter acetylcholine in both the central and peripheralnervous system. Muscarinic acetylcholine receptors are prevalentthroughout the body and five distinct muscarinic receptors (M1-M5) havebeen identified in mammals. The muscarinic receptors are known tocontain one or more allosteric sites which may alter the affinity withwhich muscarinic ligands bind to the primary binding or orthostericsites. In the central nervous system, muscarinic receptors are involvedin cognitive, behavior, sensory, motor and autonomic functions. The M4muscarinic acetylcholine receptor is predominantly expressed in thestriatum, but also in the hippocampus and cortex.

Muscarinic receptors in the central nervous system play a critical rolein mediating higher cognitive processing and control of dopaminerelease. Administration of nonselective muscarinic antagonists caninduce cognitive deficits and psychosis in humans suggesting that mAChRactivation may provide pro-cognitive and antipsychotic efficacy.Accordingly, several mAChR agonists have been developed and enteredclinical studies for the treatment of cognitive and psychiatric symptomsassociated with Alzheimer's and neuropsychiatric diseases such asschizophrenia. (Carruthers, Neuroscience & Biobehavioral Rev., 2015, 55:393-402; Jones, et al. Neuropsychopharmacology, 2012, 37: 16-42). One ofthese, the M1/M4 preferring mAChR agonist xanomeline was assessed inpatients with Alzheimer's disease, and while showing a trend forimproving cognitive deficits, did produce robust and dose-dependentreductions in hallucinations, delusions, vocal outbursts, and otherbehavioral disturbances in these patients. A subsequent study inpatients with schizophrenia demonstrated that xanomeline produced robustimprovements in positive, negative and cognitive symptoms. (Bodick, etal., Arch Neurol. 1997; 54: 465-73). Xanomeline, in addition to othermAChR agonists have been demonstrated to produce robustantipsychotic-like effects in a number of preclinical paradigms. Forinstance, xanomeline, reverses a number of dopamine driven behaviors,including amphetamine induced locomotion in rats, apomorphine inducedclimbing in mice, dopamine agonist driven turning in unilateral 6-OH-DAlesioned rats and amphetamine induced motor unrest in monkeys (withoutEPS liability). It also has been shown to inhibit A10, but not A9,dopamine cell firing and conditioned avoidance and induces c-fosexpression in prefrontal cortex and nucleus accumbens, but not instriatum in rats. These data are all suggestive of an atypicalantipsychotic-like profile. Subsequent studies with M4 knockout micehave demonstrated that the antipsychotic-like effects of xanomeline aremediated by the M4 receptor. Despite these promising clinical andpreclinical effects, xanomeline, like other muscarinic agonists,ultimately failed in clinical development due to lack of adequatereceptor subtype selectivity resulting in dose-limiting side effectsincluding disturbed gastrointestinal motility, bradycardia, nausea andvomiting.

The development of selective M4 positive allosteric modulators (PAMs) isa strategy to overcome the challenges of developing selectiveorthosteric muscarinic agonists. Indeed, studies with M4 PAMs have shownthat selective activation of M4 mAChRs can reverse bothhyperdopaminergic and hypoglutamatergic behaviors in preclinical models.Accordingly, the compounds of the present invention, which areallosteric modulators of the M4 muscarinic acetylcholine receptor, arebelieved to be useful in the treatment of Alzheimer's disease and otherdiseases mediated by the muscarinic M4 muscarinic acetylcholinereceptor.

SUMMARY OF THE INVENTION

The present invention is directed to6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-5-one compounds which areallosteric modulators of the M4 muscarinic acetylcholine receptor. Thepresent invention is also directed to uses of the compounds describedherein in the potential treatment or prevention of neurological andpsychiatric disorders and diseases in which M4 muscarinic acetylcholinereceptors are involved. The present invention is also directed tocompositions comprising these compounds. The present invention is alsodirected to uses of these compositions in the potential prevention ortreatment of such diseases in which M4 muscarinic acetylcholinereceptors are involved.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is directed to compounds of the formula I:

wherein:

-   R₁ is selected from the group consisting of:    -   (1) hydrogen;    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from the group consisting of: hydroxy,        fluoro, —CN, —O—C₁₋₆alkyl, C₃₋₆cycloalkyl,        bicycle[1.1.1]pentane, tetrahydrofuranyl, phenyl, pyridyl,        oxazolyl, —NH₂, —NH(—C₁₋₆alkyl), —N(C₁₋₆alkyl)₂, and        —N(C═O)—C₁₋₆alkyl, wherein the C₁₋₆alkyl or C₃₋₆cycloalkyl is        unsubstituted or substituted with substituents selected from the        group consisting of: fluoro, cyano, CF₃, C₁₋₆alkyl or        —O—C₁₋₆alkyl;    -   (3) a phenyl, heteroaryl or heterocyclyl ring, wherein the        phenyl, heteroaryl or heterocyclyl ring is substituted with one        or more R^(1a), R^(1b) and R^(1c), wherein R^(1a), R^(1b) and        R^(1c) are independently selected from the group consisting of:        -   (a) hydrogen,        -   (b) hydroxy,        -   (c) halogen,        -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with            substituents selected from the group consisting of: hydroxy,            cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro,            —OCH₃, —OCH₂CH₂OCH₃, —(C═O)—C₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),            —N(C₁₋₆alkyl)₂, and —N(C₃₋₆cycloalkyl),        -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with            substituents selected from the group consisting of: hydroxy,            cyclopropyl, cyclobutyl, cyclopentyl, azetidinyl, fluoro,            —OCH₃, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆alkyl)₂,            —N(C₃₋₆cycloalkyl), and —NH(C═O)(C₁₋₆alkyl),        -   (f) C₃₋₆cycloalkyl, which is unsubstituted or substituted            with substituents selected from the group consisting of:            C₁₋₆alkyl, hydroxy, cyclopropyl, cyclobutyl, cyclopentyl,            azetidinyl, fluoro, —OCH₃, —NH₂, —NH(C₁₋₆alkyl),            —N(C₁₋₆alkyl)₂, and —N(C₃₋₆cycloalkyl),        -   (g) —NH₂,        -   (h) —NH(C₁₋₆alkyl),        -   (i) —NH(C₂₋₆alkyl)-OH,        -   (j) —N(C₁₋₆alkyl)₂,        -   (k) —N(C₃₋₆cycloalkyl),        -   (l) —SO₂—C₁₋₆alkyl,        -   (m) —(C═O)H,        -   (n) —(C═O)—C₁₋₆alkyl,        -   (o) —(C═O)O—C₁₋₆alkyl, and        -   (p) —CN;-   R² and R³ are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) fluoro,    -   (3) hydroxy, and    -   (4) —CH₃;-   R⁴ is hydrogen or methyl, and R⁶ is hydrogen or methyl, or R⁴ and R⁶    are joined together with a-   —(CH₂)₂— to form a bridged ring with the piperidine ring to which    they are attached;-   R⁵ is hydrogen, or where R² is hydrogen, R³ and R⁵ may be joined    together with a —(CH₂)— to form a bridged ring with the piperidine    ring to which they are attached;-   R⁷ and R⁸ are independently selected from the group consisting of:    -   (1) hydrogen,    -   (2) C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from the group consisting of: hydroxy,        fluoro, and —OCH₃,    -   (3) —CH═CH₂,    -   (4) cyclopropyl,    -   (5) -fluoro,    -   (6) -chloro,    -   (7) -bromo,    -   (8) —CN,    -   (9) —(C═O)H, and    -   (10) —(C═O)O—C₁₋₆alkyl;-   R⁹ is selected from the group consisting of:    -   (1) hydrogen,    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from the group consisting of: hydroxy,        methoxy, fluoro, —C(C═O)O—C₁₋₆alkyl, —NH₂, —NH(C₁₋₆alkyl),        —N(C₁₋₆alkyl)₂, —C(C═O)NH₂, —C(C═O)OH, oxetanyl, or pyridyl;    -   (3) —C₃₋₆cycloalkyl,    -   (4) —C(C═O)O—C₁₋₆alkyl, and    -   (5) —P(O)(OH)₂;-   each of R¹⁰ and R¹¹ is independently selected from the group    consisting of:    -   (1) hydrogen,    -   (2) —OH,    -   (3) —CH₃,    -   (4) —CH₂OH,    -   (5) —CH₂CH₂OH, and    -   (6) —C(CH₃)₂OH,    -   or R¹⁰ and R¹¹ taken together form a cyclopropyl group, a ═CH₂        group or a keto group;-   or a pharmaceutically acceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIa:

wherein R¹, R², R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIb:

wherein R¹, R², R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIc:

wherein R¹, R², R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIIa:

wherein R¹, R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIIb:

wherein R¹, R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIIc:

wherein R¹, R⁷, R⁸ and R⁹ are defined herein; or a pharmaceuticallyacceptable salt thereof.

An embodiment of the present invention includes compounds of the formulaIIIa:

where in R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIIIb:

wherein R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIIIc:

wherein R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIVa:

wherein R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIVb:

wherein R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds of the formulaIVc:

wherein R¹ and R⁹ are defined herein; or a pharmaceutically acceptablesalt thereof.

An embodiment of the present invention includes compounds wherein R¹ isselected from the group consisting of: benzodioxolyl, benzoimidazolyl,benzoxazolyl, benzooxazinone, benzooxazolone, benzothiazolyl, chromanyl,cyclopentapyridinyl, dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl,dihydrobenzo[1,4]oxazinyl, dihydrofuropyridinyl, dihydroisobenzofuranyl,dihydroisoquinolinone, dihydropyranopyridinyl, dihydroimidazopyridine,dihydropyrido[1,4]oxazinyl, dihydroquinolinone, indazolyl, indanyl,indolyl, isochromanone, isobenzofuranone, isochromanyl, isoindolinyl,isoxazolyl, oxoisoindolinyl, phenyl, pyrazolopyridinyl, pyrazolyl,pyridyl, pyrrolopyridinyl, pyrimidinyl, quinolinone, quinolinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl, andtetrahydropyranyl,

which is substituted with one or more of R^(1a), R^(1b) and R^(1c).

An embodiment of the present invention includes compounds wherein R¹ isphenyl or pyridyl, which is substituted with R^(1a), R^(1b) and R_(1c),wherein R^(1a), R^(1b) and R^(1c) are independently selected from thegroup consisting of

-   -   (a) hydrogen,    -   (b) hydroxyl,    -   (c) halogen,    -   (d) C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from the group consisting of: hydroxy,        fluoro, and —OCH₃,    -   (e) —O—C₁₋₆alkyl, which is unsubstituted or substituted with        substituents selected from the group consisting of: hydroxy,        fluoro, and —OCH₃,    -   (f) C₃₋₆cycloalkyl, which is unsubstituted or substituted with a        substituent selected from the group consisting of: C₁₋₆alkyl and        hydroxy; and    -   (g) —CN.

An embodiment of the present invention includes compounds wherein R¹ isphenyl or pyridyl, which is substituted with R^(1a), R_(1b) and R^(1c),wherein R^(1a), R^(1b) and R^(1c) are independently selected from thegroup consisting of

-   -   (a) hydrogen,    -   (b) hydroxyl,    -   (c) halogen,    -   (d) C₁₋₃alkyl, which is unsubstituted or substituted with a        substituent selected from the group consisting of: hydroxy, 1-3        fluoro, and —OCH₃,    -   (e) —O—C₁₋₃alkyl, which is unsubstituted or substituted with a        substituent selected from the group consisting of: 1-3 fluoro,        and —OCH₃, and    -   (g) —CN.

An embodiment of the present invention includes compounds wherein R¹ isselected from the group consisting of:

-   -   (a) hydrogen,    -   (b) C₁₋₆alkyl, which is unsubstituted or substituted with        cyclopropyl which is unsubstituted or substituted with        substituents selected from the group consisting of: fluoro and        C₁₋₆alkyl,    -   (c) dihydrofuropyridinyl,    -   (d) indazole, which is unsubstituted or substituted with        C₁₋₃alkyl,    -   (e) tetrahydroisobenzofuranyl, which is unsubstituted or        substituted with C₁₋₃alkyl,    -   (f) phenyl, which is unsubstituted or substituted with C₁₋₃alkyl        or —CN, and    -   (g) pyridyl, which is unsubstituted or substituted with        C₁₋₃alkyl or —O—C₁₋₃alkyl.

An embodiment of the present invention includes compounds wherein R¹ isselected from the group consisting of:

-   -   (a) C₁₋₆alkyl, which is unsubstituted or substituted with        cyclopropyl, methyl-cyclopropyl, dimethyl-cyclopropyl,        methyl-fluoro-cyclopropyl, methyl-difluoro-cyclopropyl, or        dimethyl-difluoro-cyclopropyl,    -   (b) indazole, which is unsubstituted or substituted with        C₁₋₃alkyl,    -   (c) tetrahydroisobenzofuranyl, which is unsubstituted or        substituted with C₁₋₃ alkyl,    -   (d) phenyl, which is unsubstituted or substituted with C₁₋₃alkyl        or —CN, and    -   (e) pyridyl, which is unsubstituted or substituted with        C₁₋₃alkyl or —O—C₁₋₃alkyl.

An embodiment of the present invention includes compounds wherein R¹ isphenyl, which is unsubstituted or substituted with —CN. An embodiment ofthe present invention includes compounds wherein R¹ is pyridyl, which isunsubstituted or substituted with —OCH₃.

An embodiment of the present invention includes compounds wherein R¹ isdihydrofuropyridinyl. An embodiment of the present invention includescompounds wherein R¹ is indazole, which is unsubstituted or substitutedwith methyl. An embodiment of the present invention includes compoundswherein R¹ is tetrahydroisobenzofuranyl. An embodiment of the presentinvention includes compounds wherein R¹ is dihydroisobenzofuranyl. Anembodiment of the present invention includes compounds wherein R¹ isCH₂-(methyl)cyclopropyl. An embodiment of the present invention includescompounds wherein R¹ is CH₂-(dimethyl)-cyclopropyl. An embodiment of thepresent invention includes compounds wherein R¹ isCH₂-(methyl-fluoro)cyclopropyl. An embodiment of the present inventionincludes compounds wherein R¹ is CH₂-(methyl-difluoro)cyclopropyl. Anembodiment of the present invention includes compounds wherein R¹ isCH₂-(dimethyl-difluoro)cyclopropyl.

An embodiment of the present invention includes compounds wherein R² andR³ are each hydrogen. An embodiment of the present invention includescompounds wherein R² is fluoro and R³ is hydrogen. An embodiment of thepresent invention includes compounds wherein R² is —CH₃ and R³ ishydrogen. An embodiment of the present invention includes compoundswherein R² is fluoro and R³ is fluoro.

An embodiment of the present invention includes compounds wherein R⁴ ishydrogen and R⁶ is hydrogen. An embodiment of the present inventionincludes compounds wherein R⁴ and R⁶ are joined together with a —(CH₂)₂—to form a bridged ring with the piperidine ring to which they areattached.

An embodiment of the present invention includes compounds wherein R⁵ ishydrogen. An embodiment of the present invention includes compoundswherein R² is hydrogen, and R³ and R⁵ are joined together with a —(CH₂)—to form a bridged ring with the piperidine ring to which they areattached. An embodiment of the present invention includes compoundswherein R², R³, R⁴, R⁵ and R⁶ are each hydrogen.

An embodiment of the present invention includes compounds wherein R⁷ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl,    -   (4) —CH₂OH,    -   (5) —CH₂F,    -   (6) —CHF₂,    -   (7) —CF₃,    -   (8) —CH═CH₂,    -   (9) cyclopropyl,    -   (10) -fluoro,    -   (11) -chloro,    -   (12) -bromo,    -   (13) —CN,    -   (14) —(C═O)H, and    -   (15) —(C═O)O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R⁷ is—CH₃. An embodiment of the present invention includes compounds whereinR⁷ is —CF₃.

An embodiment of the present invention includes compounds wherein R⁸ isselected from the group consisting of:

-   -   (1) hydrogen,    -   (2) methyl,    -   (3) ethyl,    -   (4) —CH₂OH,    -   (5) —CH₂F,    -   (6) —CHF₂,    -   (7) —CF₃, and    -   (8) —(C═O)O—C₁₋₆alkyl.

An embodiment of the present invention includes compounds wherein R⁸ ishydrogen. An embodiment of the present invention includes compoundswherein R⁸ is —CH₃.

An embodiment of the present invention includes compounds wherein R⁹ isselected from the group consisting of:

-   -   (1) hydrogen, and    -   (2) —C₁₋₆alkyl, which is unsubstituted or substituted with        hydroxy, methoxy, 1-3 fluoro.

An embodiment of the present invention includes compounds wherein R⁹ ishydrogen. An embodiment of the present invention includes compoundswherein R⁹ is methyl. An embodiment of the present invention includescompounds wherein R⁹ is —CH₂CH₂OH.

An embodiment of the present invention includes compounds wherein R¹⁰ ishydrogen and R¹¹ is hydrogen. An embodiment of the present inventionincludes compounds wherein R¹⁰ is —CH₃ and R¹¹ is hydrogen. Anembodiment of the present invention includes compounds wherein R¹⁰ is—CH₃ and R¹¹ is —CH₃. An embodiment of the present invention includescompounds wherein R¹⁰ is —CH₂OH and R¹¹ is hydrogen. An embodiment ofthe present invention includes compounds wherein R¹⁰ and R¹¹ takentogether form a cyclopropyl group. An embodiment of the presentinvention includes compounds wherein R¹⁰ and R¹¹ taken together form a═CH₂ group. An embodiment of the present invention includes compoundswherein R¹⁰ and R¹¹ taken together form a keto group.

Certain embodiments of the present invention include a compound which isselected from the group consisting of the subject compounds of theExamples herein or a pharmaceutically acceptable salt thereof.

The compounds of the present invention may contain one or moreasymmetric centers and can thus occur as racemates and racemic mixtures,single enantiomers, diastereomeric mixtures and individualdiastereomers. Additional asymmetric centers may be present dependingupon the nature of the various substituents on the molecule. Each suchasymmetric center will independently produce two optical isomers and itis intended that all of the possible optical isomers and diastereomersin mixtures and as pure or partially purified compounds are includedwithin the ambit of this invention. The present invention is meant tocomprehend all such isomeric forms of these compounds. Likewise, thepresent invention includes tautomeric forms of the compounds disclosedherein. Formula I shows the structure of the class of compounds withoutspecific stereochemistry. At least some of the chemical names ofcompounds of the invention as set forth in this application may havebeen generated on an automated basis by use of commercially availablechemical naming software programs, and have not been independentlyverified.

The independent syntheses of these diastereomers or theirchromatographic separations may be achieved as known in the art byappropriate modification of the methodology disclosed herein. Theirabsolute stereochemistry may be determined by the x-ray crystallographyof crystalline products or crystalline intermediates which arederivatized, if necessary, with a reagent containing an asymmetriccenter of known absolute configuration. If desired, racemic mixtures ofthe compounds may be separated so that the individual enantiomers areisolated. The separation can be carried out by methods well known in theart, such as the coupling of a racemic mixture of compounds to anenantiomerically pure compound to form a diastereomeric mixture,followed by separation of the individual diastereomers by standardmethods, such as fractional crystallization or chromatography. Thecoupling reaction is often the formation of salts using anenantiomerically pure acid or base. The diasteromeric derivatives maythen be converted to the pure enantiomers by cleavage of the addedchiral residue. The racemic mixture of the compounds can also beseparated directly by chromatographic methods utilizing chiralstationary phases, which methods are well known in the art.Alternatively, any enantiomer of a compound may be obtained bystereoselective synthesis using optically pure starting materials orreagents of known configuration by methods well known in the art.

As appreciated by those of skill in the art, halogen or halo as usedherein are intended to include fluoro, chloro, bromo and iodo.Similarly, C₁₋₆, as in C₁₋₆alkyl is defined to identify the group ashaving 1, 2, 3, 4, 5 or 6 carbons in a linear or branched arrangement,such that C₁₋₆alkyl specifically includes methyl, ethyl, n-propyl,iso-propyl, n-butyl, iso-butyl, tert-butyl, pentyl, and hexyl. Likewise,—N(C₃₋₆cycloalkyl) refers to the presence of a nitrogen-containingsaturated such a pyrrolidine or piperidine. Substituents (such asR^(1a), R^(1b) and R_(1c)) may be absent if the valency of the group towhich they are attached does not permit such substitution. A group whichis designated as being independently substituted with substituents maybe independently substituted with multiple numbers of such substituents.

The term “heteroaryl” as used herein represents a stable monocyclic,bicyclic or tricyclic ring of up to 7 atoms in each ring, wherein atleast one ring is aromatic and contains carbon and from 1 to 4heteroatoms selected from the group consisting of O, N and S. In anotherembodiment, the term heteroaryl refers to a monocyclic, bicyclic ortricyclic aromatic ring of 5- to 14-ring atoms of carbon and from one tofour heteroatoms selected from O, N, or S. As with the definition ofheterocyclyl below, “heteroaryl” is also understood to include theN-oxide derivative of any nitrogen-containing heteroaryl. In cases wherethe heteroaryl substituent is bicyclic and one ring is non-aromatic, inone embodiment, the attachment is via a carbon atom of the aromaticring. Examples of heteroaryl include but are not limited tobenzodioxolyl, benzofuranyl, benzofurazanyl, benzoimidazolyl,benzimidazolonyl, benzopyrazolyl, benzothiazolyl, benzotriazolyl,benzothiophenyl, benzoxazepinyl, benzooxazinonyl, benzooxazolonyl,benzoxazolyl, carbazolyl, carbolinyl, chromanyl, cinnolinyl,cyclopentapyridinyl, dihydrobenzo[1,4]dioxinyl, dihydrobenzofuranyl,dihydrobenzo[1,4]oxazinyl, dihydrofuropyridinyl, dihydroindolyl,dihydroisobenzofuranyl, dihydroisoquinolinonyl, dihydropyranopyridinyl,dihydroimidazopyridinyl, dihydropyrido[1,4]oxazinyl, dihydroquinolinone,furanyl, imidazolyl, indolinyl, indolyl, indanyl, indolazinyl,indazolyl, isobenzofuranyl, isobenzofuranonyl, isochromanonyl,isochromanyl, isoindolinyl, isoindolyl, isoxazolinyl, isoxazolyl,isoquinolyl, isothiazolyl, isoxazolyl, naphthpyridinyl, oxadiazolyl,oxazolyl, oxazolinyl, oxetanyl, oxoisoindolinyl, pyrazinyl,pyrazolopyridinyl, pyrazolyl, pyridazinyl, pyridopyridinyl, pyridazinyl,pyridyl, pyrimidinyl, pyrimidyl, pyrrolopyridinyl, pyrrolyl,quinazolinyl, quinolyl, quinoxalinyl, tetrahydrobenzooxepinyl,tetrahydroisoquinolinyl, tetrahydropyranyl,tetrahydroquinoxalinyl,tetrazolyl, tetrazolopyridyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and N-oxides thereof, and wherein the saturated heterocyclicmoieties include azetidinyl, 1,4-dioxanyl, hexahydroazepinyl,piperazinyl, piperidinyl, pyridin-2-onyl, pyrrolidinyl, morpholinyl,tetrahydrofuranyl, thiomorpholinyl, and tetrahydrothienyl, and N-oxidesthereof.

“Heterocyclyl” means a non-aromatic saturated monocyclic, bicyclic,tricyclic or spirocyclic ring system comprising up to 7 atoms in eachring, or contains 3 to 14, or 5 to 10 ring atoms, in which one or moreof the atoms in the ring system is an element other than carbon, forexample, nitrogen, oxygen, phosphor or sulfur, alone or in combination.There are no adjacent oxygen and/or sulfur atoms present in the ringsystem. In one embodiment, the heterocyclyls contain about 5 to about 6ring atoms. The heterocyclyl may be fused with an aromatic aryl groupsuch as phenyl or heterocyclenyl. The heterocyclyl is optionally bridged(i.e., forming a bicyclic moiety), for example with a methylene,ethylene or propylene bridge. The prefix aza, oxa or thia before theheterocyclyl root name means that at least a nitrogen, oxygen or sulfuratom, respectively, is present as a ring atom. The nitrogen or sulfuratom of the heterocyclyl can be optionally oxidized to the correspondingN-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitablemonocyclic heterocyclyl rings include piperidyl, pyrrolidinyl,piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1,4-dioxanyl,tetrahydrofuranyl, tetrahydropyran, tetrahydrothiophenyl, lactam,lactone, and the like. “Heterocyclyl” also includes heterocyclyl ringsas described above wherein ═O replaces two available hydrogens on thesame ring carbon atom.

The present invention also includes all pharmaceutically acceptableisotopic variations of a compound of the Formula I in which one or moreatoms is replaced by atoms having the same atomic number, but an atomicmass or mass number different from the atomic mass or mass numberusually found in nature. Such compounds are identical to those disclosedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that can beincorporated into the compounds of the invention include isotopes ofhydrogen such as ²H and ³H, carbon such as ¹¹C, ¹³C and ¹⁴C, nitrogensuch as ¹³N and ¹⁵N, oxygen such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus such as³²P, sulfur such as ³⁵S, fluorine such as ¹⁸F, iodine such as ¹²³I and¹²⁵I, and chlorine such as ³⁶Cl. Certain isotopically-labelled compoundsof Formula I, for example those incorporating a radioactive isotope, areuseful in drug and/or substrate tissue distribution studies. Theradioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, areparticularly useful for this purpose in view of their ease ofincorporation and ready means of detection. Substitution with heavierisotopes such as deuterium, i.e. ²H, may afford certain therapeuticadvantages resulting from greater metabolic stability, for example,increased in vivo half-life or reduced dosage requirements, and hencemay be preferred in some circumstances. Substitution with positronemitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and ¹³N, can be useful inPositron Emission Topography (PET) studies for examining substratereceptor occupancy. An embodiment of the present invention includescompounds that are substituted with a positron emitting isotope. Anembodiment of the present invention includes compounds that aresubstituted with a ¹¹C isotope. An embodiment of the present inventionincludes compounds that are substituted with an ¹⁸F isotope. In thecompounds of the invention, the atoms may exhibit their natural isotopicabundances, or one or more of the atoms may be artificially enriched ina particular isotope having the same atomic number, but an atomic massor mass number different from the atomic mass or mass numberpredominantly found in nature. The present invention is meant to includeall suitable isotopic variations of the compounds of the invention. Forexample, different isotopic forms of hydrogen (H) include protium (¹H)and deuterium (²H). Protium is the predominant hydrogen isotope found innature. Enriching for deuterium may afford certain therapeuticadvantages, such as increasing in vivo half-life or reducing dosagerequirements, or may provide a compound useful as a standard forcharacterization of biological samples. Isotopically-enriched compoundsof the invention can be prepared without undue experimentation byconventional techniques well known to those skilled in the art or byprocesses analogous to those described in the schemes and examplesherein using appropriate isotopically-enriched reagents and/orintermediates.

Those skilled in the art will recognize those instances in which thecompounds of the invention may form salts. In such instances, anotherembodiment provides pharmaceutically acceptable salts of the compoundsof the invention. Thus, reference to a compound of the invention hereinis understood to include reference to salts thereof, unless otherwiseindicated. The term “pharmaceutically acceptable salts” refers to saltsprepared from pharmaceutically acceptable non-toxic bases or acidsincluding inorganic or organic bases and inorganic or organic acids. Inaddition, when a compound of the invention contains both a basic moiety,such as, but not limited to a pyridine or imidazole, and an acidicmoiety, such as, but not limited to a carboxylic acid, zwitterions(“inner salts”) may be formed and are included within the presentinvention. Salts derived from inorganic bases include aluminum,ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganicsalts, manganous, potassium, sodium, zinc, and the like. Particularembodiments include the ammonium, calcium, magnesium, potassium, andsodium salts. Salts in the solid form may exist in more than one crystalstructure, and may also be in the form of hydrates or solvates. Saltsderived from pharmaceutically acceptable organic non-toxic bases includesalts of primary, secondary, and tertiary amines, substituted aminesincluding naturally occurring substituted amines, cyclic amines, andbasic ion exchange resins, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylene-diamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethyl-morpholine, N-ethylpiperidine, glucamine, glucosamine,histidine, hydrabamine, isopropylamine, lysine, methylglucamine,morpholine, piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine,tromethamine, and the like. When the compound of the present inventionis basic, salts may be prepared from pharmaceutically acceptablenon-toxic acids, including inorganic and organic acids. Such acidsinclude acetic, benzenesulfonic, benzoic, camphorsulfonic, citric,ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric,isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic,nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric,p-toluenesulfonic acid, and the like. Particular embodiments include thecitric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric,fumaric, and tartaric acids. It will be understood that, as used herein,references to the compounds of Formula I are meant to also include thepharmaceutically acceptable salts. Salts of the compounds of theinvention may be formed by methods known to those of ordinary skill inthe art, for example, by reacting a compound of the invention with anamount of acid or base, such as an equivalent amount, in a medium suchas one in which the salt precipitates or in an aqueous medium followedby lyophilization.

Exemplifying the invention is the use of the compounds disclosed in theExamples and herein. Specific compounds within the present inventioninclude a compound which is selected from the group consisting of thecompounds disclosed in the following Examples and pharmaceuticallyacceptable salts thereof and individual enantiomers or diastereomersthereof.

As used herein, the term “M4 muscarinic acetylcholine receptor” refersto one of the five subtypes of the muscarinic acetylcholine receptor,which is from the superfamily of G-protein coupled receptors. The familyof muscarinic receptors is described, for example, in Pharmacol Ther,1993, 58:319-379; Eur J Pharmacol, 1996, 295:93-102, and Mol Pharmacol,2002, 61:1297-1302. The muscarinic receptors are known to contain one ormore allosteric sites, which may alter the affinity with whichmuscarinic ligands bind to the primary binding or orthosteric sites.See, e.g., S. Lazareno, et al., Mol Pharmacol, 2002, 62:6, 1491-1505.

As used herein, the terms “positive allosteric modulator” and“allosteric potentiator” are used interchangeably, and refer to a ligandwhich interacts with an allosteric site of a receptor to augment theresponse produced by the endogenous ligand at the orthosteric bindingsite. The compounds of the invention are allosteric modulators of the M4muscarinic acetylcholine receptor, including as positive allostericmodulators of the M4 muscarinic acetylcholine receptor and silentallosteric modulators of the M4 muscarinic acetylcholine receptor. Someof the compounds of the invention are agonists of the M4 muscarinicacetylcholine receptor. Some of the compounds of the invention areallosteric modulators of the M1 muscarinic acetylcholine receptor, ormay be agonists of the M1 muscarinic acetylcholine receptor. Forexample, a modulator or potentiator may directly or indirectly augmentthe response produced by the endogenous ligand (such as acetylcholine orxanomeline) at the orthosteric site of the M4 muscarinic acetylcholinereceptor in an animal, in particular, a human.

The actions of ligands at allosteric receptor sites may also beunderstood according to the “allosteric ternary complex model,” as knownby those skilled in the art. The allosteric ternary complex model isdescribed with respect to the family of muscarinic receptors in Birdsallet al, Life Sciences, 2001, 68:2517-2524. For a general description ofthe role of allosteric binding sites, see Christopoulos, Nature Reviews:Drug Discovery, 2002, 1:198-210.

It is believed that the compounds of the invention bind to an allostericbinding site that is distinct from the orthosteric acetylcholine site ofthe M4 muscarinic acetylcholine receptor, thereby augmenting theresponse produced by the endogenous ligand acetylcholine at theorthosteric site of the M4 muscarinic acetylcholine receptor. It is alsobelieved that the compounds of the invention bind to an allosteric sitewhich is distinct from the xanomeline site of the M4 muscarinicacetylcholine receptor, thereby augmenting the response produced by theendogenous ligand xanomeline at the orthosteric site of the M4muscarinic acetylcholine receptor.

The present invention is also directed to the use of the compoundsdisclosed herein as modulators of M4 muscarinic acetylcholine receptoractivity. The subject compounds and pharmaceutically acceptable saltsthereof are useful in a method of M4 modulating muscarinic acetylcholinereceptor activity in a subject such as a mammal comprising theadministration of an amount of the compound. In addition to primates,especially humans, a variety of other mammals may be administered with acompound of the present invention. The present invention is directed toa compound of the present invention or a pharmaceutically acceptablesalt thereof that could be useful in therapy. The present invention mayfurther be directed to a use of a compound of the present invention or apharmaceutically acceptable salt thereof for the manufacture of amedicament for modulating M4 muscarinic acetylcholine receptor activityor treating the disorders and diseases noted herein in humans andanimals.

A subject administered with a compound of the present invention, or apharmaceutically acceptable salt thereof, is generally a mammal, such asa human being, male or female. The amount of compound administered tothe subject is an amount sufficient to modulate the M4 muscarinicacetylcholine receptor in the subject. In an embodiment, the amount ofcompound can be an “effective amount” or “therapeutically effectiveamount”, wherein the subject compound or pharmaceutical composition isadministered in an amount that will elicit the biological or medicalresponse of a tissue, system, animal or human that is being sought bythe researcher, veterinarian, medical doctor or other clinician, orotherwise inhibiting the noted disease and thus producing the desiredtherapeutic, ameliorative, inhibitory or preventative effect. Aneffective amount does not necessarily include considerations of toxicityand safety related to the administration of the compound. It isrecognized that one skilled in the art may affect neurological andpsychiatric disorders associated with M4 muscarinic acetylcholinereceptor modulation by treating a subject presently afflicted with thedisorders, or by prophylactically treating a subject likely to beafflicted with the disorders, with an effective amount of a compound ofthe present invention. As used herein, the terms “treatment” and“treating” refer to all processes wherein there may be a slowing,interrupting, arresting, controlling, or stopping of the progression ofthe neurological and psychiatric disorders described herein, but doesnot necessarily indicate a total elimination of all disorder symptoms,as well as the prophylactic therapy of the mentioned conditions,particularly in a subject that is predisposed to such disease ordisorder. The terms “administration of” and “administering” a compoundshould be understood to mean providing a compound of the invention or aprodrug of a compound of the invention to the subject. The term“dysfunction” refers to abnormality or impairment in the function of thenoted system.

The term “composition” as used herein is intended to encompass a productcomprising the specified ingredients in the specified amounts, as wellas any product which results, directly or indirectly, from combinationof the specified ingredients in the specified amounts. Such term isintended to encompass a product comprising the active ingredient(s), andthe inert ingredient(s) that make up the carrier, as well as any productwhich results, directly or indirectly, from combination, complexation oraggregation of any two or more of the ingredients, or from dissociationof one or more of the ingredients, or from other types of reactions orinteractions of one or more of the ingredients. Accordingly, thecompositions of the present invention encompass any composition made byadmixing a compound of the present invention and a pharmaceuticallyacceptable carrier. By “pharmaceutically acceptable” it is meant thecarrier, diluent or excipient must be compatible with the otheringredients of the formulation and not deleterious to the recipientthereof.

The utility of the compounds in accordance with the present invention asmodulators of M4 muscarinic acetylcholine receptors may be readilydetermined without undue experimentation by methodology well known inthe art, including monitoring the mobilization of intracellular Ca++,determining the levels of intracellular cAMP, or quantiting the exchangeof GDP for [35S]γGTP.

In a typical experiment the M4 muscarinic acetylcholine receptormodulating activity of the compounds of the present invention wasdetermined in accordance with the following experimental method. CHO-K1cells stably transfected with human M4 receptor and chimeric G-proteinGαqi5 (Coward P, et al., Analytical Biochemistry, 270:242-248 (1999))are thawed from liquid N₂ storage, resuspended in growth medium, platedin black, clear bottom 384 well plates, and incubated 16-20 hours at 37°C., 5% CO₂. On the day of assay, growth medium is removed, the cells arewashed 2 times with wash buffer, and cells are incubated in dye loadingbuffer at 37° C., 5% CO₂ for ˜1 hour. Following dye loading the cellplates are placed in a FLIPR Tetra instrument and while monitoring dyefluorescence (excitation 470-495 nM/emission 515-575 nM), 10 uL of testsubstance at increasing concentrations is added, and fluorescence valuesare recorded for 4 min. Next, 10 uL of acetylcholine is added (finalconcentration calculated so as to achieve 20% of the maximumacetycholine response), and the fluorescence reading is continued for3.5 min. In some cases, a third addition of acetylcholine (finalconcentration calculated to achieve 70% of the maximal acetylcholineresponse) is performed. The resulting dose response curves are fit to a4 parameter logistic equation and the final result is determined as theinflection point (IP) of the curve

The intrinsic M4 muscarinic acetylcholine receptor modulating activityof a compound which may be used in the present invention may bedetermined by these assays.

All of the final compounds of the following examples had activity in thehuman FLIPR-based M4 PAM assay with an IP of about 5 nM to 15000 nMagainst the human M4 muscarinic acetylcholine receptor. Additional datais provided in the following Examples. Such a result is indicative ofthe intrinsic activity of the compounds in use as a modulating the humanM4 muscarinic acetylcholine receptor. In general, one of ordinary skillin the art would appreciate that a substance is considered toeffectively modulate the human M4 muscarinic acetylcholine receptor ifit has an IP of less than about 50 μM, or more specifically less thanabout 15000 nM.

The M4 muscarinic acetylcholine receptor has been implicated in a widerange of biological functions. This has suggested a potential role forthese receptors in a variety of disease processes in humans or otherspecies. The compounds of the present invention could thereforepotentially have utility in treating, preventing, ameliorating,controlling or reducing the risk of a variety of neurological andpsychiatric disorders associated with M4 muscarinic acetylcholinereceptors, including one or more of the following conditions ordiseases, and other diseases related to general M4 muscarinicacetylcholine receptor system dysfunction.

Potential conditions or disorders for which the compounds of theinvention may be useful further include one or more of the followingconditions or diseases: Alzheimer's disease (including mild Alzheimer'sdisease, moderate Alzheimer's disease and severe Alzheimer's disease),olfactory impairment associated with Alzheimer's disease, Down'ssyndrome, olfactory impairment associated with Down's syndrome,Parkinson's disease, olfactory impairment associated with Parkinson'sdisease, stroke, microgliosis brain inflammation, pre-senile dementia,senile dementia, progressive supranuclear palsy, cortical basaldegeneration, β-amyloid angiopathy, cerebral amyloid angiopathy,hereditary cerebral hemorrhage, cognitive disorders (including mildcognitive impairment), glaucoma, amyloidosis, type II diabetes,diabetes-associated amyloidogenesis, scrapie, bovine spongiformencephalitis, traumatic brain injury, Creutzfeld-Jakob disease,schizophrenia, sleep disorders, pain disorders (including acute pain,inflammatory pain and neuropathic pain), pulmonary hypertension, chronicobstructive pulmonary disease (COPD), asthma, urinary incontinence,glaucoma, schizophrenia, Trisomy 21 (Down Syndrome), cerebral amyloidangiopathy, degenerative dementia, Hereditary Cerebral Hemorrhage withAmyloidosis of the Dutch-Type (HCHWA-D), Creutzfeld-Jakob disease, priondisorders, amyotrophic lateral sclerosis, progressive supranuclearpalsy, head trauma, stroke, pancreatitis, inclusion body myositis, otherperipheral amyloidoses, diabetes, autism, atherosclerosis, toleranceand/or dependence to opioid treatment of pain, and for treatment ofwithdrawal syndrome of e.g., alcohol, opioids, and cocaine, Huntington'sdisease, drug-induced dyskinesias.

Potential conditions or disorders for which the compounds of theinvention may be useful further include one or more of the followingconditions or diseases: schizophrenia or psychosis includingschizophrenia (paranoid, disorganized, catatonic or undifferentiated),schizophreniform disorder, schizoaffective disorder, delusionaldisorder, brief psychotic disorder, shared psychotic disorder, psychoticdisorder due to a general medical condition and substance-induced ordrug-induced (phencyclidine, ketamine and other dissociativeanaesthetics, amphetamine and other psychostimulants and cocaine)psychosispsychotic disorder, psychosis associated with affectivedisorders, brief reactive psychosis, schizoaffective psychosis,“schizophrenia-spectrum” disorders such as schizoid or schizotypalpersonality disorders, or illness associated with psychosis (such asmajor depression, manic depressive (bipolar) disorder, Alzheimer'sdisease and post-traumatic stress syndrome), including both the positiveand the negative symptoms of schizophrenia and other psychoses;cognitive disorders including dementia (associated with Alzheimer'sdisease, ischemia, multi-infarct dementia, trauma, vascular problems orstroke, HIV disease, Parkinson's disease, Levodopa induced dyskinesia,other drug induced dyskinesia (e.g. tardive dyskinesias), Huntington'sdisease, Pick's disease, Creutzfeldt-Jacob disease, perinatal hypoxia,other general medical conditions or substance abuse); delirium, amnesticdisorders or age related cognitive decline; delusional disorder, sharedpsychotic disorder, catastrophic schizophrenia, postpartum psychosis,psychotic depression, psychotic break, tardive psychosis, myxedematouspsychosis, occupational psychosis, menstrual psychosis, secondarypsychotic disorder, bipolar I disorder with psychotic features, andsubstance-induced psychotic disorder; major depressive disorder,affective disorder, bipolar disorder, electrolyte disorder, neurologicaldisorder, hypoglycemia, AIDS, lupus, and post-traumatic stress disorder;brain tumor, dementia with Lewy bodies, multiple sclerosis, sarcoidosis,Lyme disease, syphilis, Alzheimer's disease, Parkinson's disease, andanti-NMDA receptor encephalitis. Thus, in another specific embodiment,the present invention provides a method for treating schizophrenia orpsychosis comprising administering to a patient in need thereof aneffective amount of a compound of the present invention. At present, thetext revision of the fourth edition of the Diagnostic and StatisticalManual of Mental Disorders (DSM-IV-TR) (2000, American PsychiatricAssociation, Washington D.C.) provides a diagnostic tool that includesparanoid, disorganized, catatonic or undifferentiated schizophrenia andsubstance-induced psychotic disorder. As used herein, the term“schizophrenia or psychosis” includes treatment of those mentaldisorders as described in DSM-IV-TR. The skilled artisan will recognizethat there are alternative nomenclatures, nosologies and classificationsystems for mental disorders, and that these systems evolve with medicaland scientific progress. Thus the term “schizophrenia or psychosis” isintended to include like disorders that are described in otherdiagnostic sources.

Potential conditions or disorders for which the compounds of theinvention may be useful further include one or more of the followingconditions or diseases: mood disorders, such as depression or moreparticularly depressive disorders, for example, single episodic orrecurrent major depressive disorders and dysthymic disorders, or bipolardisorders, for example, bipolar I disorder, bipolar II disorder andcyclothymic disorder, mood disorders due to a general medical condition,and substance-induced mood disorders; affective neurosis; depressiveneurosis; anxiety neurosis; anxiety disorders including acute stressdisorder, agoraphobia, generalized anxiety disorder,obsessive-compulsive disorder, panic attack, panic disorder,post-traumatic stress disorder, separation anxiety disorder, socialphobia, specific phobia, substance-induced anxiety disorder and anxietydue to a general medical condition; acute neurological and psychiatricdisorders such as cerebral deficits subsequent to cardiac bypass surgeryand grafting, stroke, ischemic stroke, cerebral ischemia, spinal cordtrauma, head trauma, perinatal hypoxia, cardiac arrest, hypoglycemicneuronal damage; idiopathic and drug-induced Parkinson's disease;muscular spasms and disorders associated with muscular spasticityincluding tremors, epilepsy, convulsions, seizure disorders, absenceseisures, complex partial and generalized seizures; Lennox-Gastautsyndrome; cognitive disorders including dementia (associated withAlzheimer's disease, ischemia, trauma, vascular problems or stroke, HIVdisease, Parkinson's disease, Huntington's disease, Pick's disease,Creutzfeldt-Jacob disease, perinatal hypoxia, other general medicalconditions or substance abuse); delirium, amnestic disorders or agerelated cognitive decline; dissociative disorders including multiplepersonality syndromes and psychogenic amnesias; substance-relateddisorders, substance use, substance abuse, substance seeking, substancereinstatement, all types of psychological and physical addictions andaddictive behaviors, reward-related behaviors (includingsubstance-induced delirium, persisting dementia, persisting amnesticdisorder, psychotic disorder or anxiety disorder; tolerance, addictivefeeding, addictive feeding behaviors, binge/purge feeding behaviors,dependence, withdrawal or relapse from substances including alcohol,amphetamines, cannabis, cocaine, hallucinogens, inhalants, morphine,nicotine, opioids, phencyclidine, sedatives, hypnotics or anxiolytics);appetite, taste, eating or drinking disorders; movement disorders,including akinesias and akinetic-rigid syndromes (including Parkinson'sdisease, drug-induced parkinsonism, postencephalitic parkinsonism,progressive supranuclear palsy, multiple system atrophy, corticobasaldegeneration, parkinsonism-ALS dementia complex and basal gangliacalcification), chronic fatigue syndrome, fatigue, including Parkinson'sfatigue, multiple sclerosis fatigue, fatigue caused by a sleep disorderor a circadian rhythm disorder, medication-induced parkinsonism (such asneuroleptic-induced parkinsonism, neuroleptic malignant syndrome,neuroleptic-induced acute dystonia, neuroleptic-induced acute akathisia,neuroleptic-induced tardive dyskinesia and medication-induced posturaltremor), Gilles de la Tourette's syndrome, epilepsy, and dyskinesias[including tremor (such as rest tremor, essential tremor, posturaltremor and intention tremor), chorea (such as Sydenham's chorea,Huntington's disease, benign hereditary chorea, neuroacanthocytosis,symptomatic chorea, drug-induced chorea and hemiballism), myoclonus(including generalised myoclonus and focal myoclonus), tics (includingsimple tics, complex tics and symptomatic tics), restless leg syndromeand dystonia (including generalised dystonia such as iodiopathicdystonia, drug-induced dystonia, symptomatic dystonia and paroxymaldystonia, and focal dystonia such as blepharospasm, oromandibulardystonia, spasmodic dysphonia, spasmodic torticollis, axial dystonia,dystonic writer's cramp and hemiplegic dystonia); neurodegenerativedisorders including nosological entities such asdisinhibition-dementia-parkinsonism-amyotrophy complex;pallido-ponto-nigral degeneration; epilepsy; seizure disorders;attention deficit/hyperactivity disorder (ADHD); conduct disorder;migraine (including migraine headache); headache; hyperalgesia; pain;enhanced or exaggerated sensitivity to pain such as hyperalgesia,causalgia, and allodynia; acute pain; burn pain; atypical facial pain;neuropathic pain; back pain; complex regional pain syndrome I and II;arthritic pain; sports injury pain; pain related to infection e.g. HIV,post-chemotherapy pain; post-stroke pain; post-operative pain;neuralgia; emesis, nausea, vomiting; gastric dyskinesia; gastric ulcers;Kallman's syndrome (anosmia); asthma; cancer; conditions associated withvisceral pain such as irritable bowel syndrome, and angina; eatingdisorders; urinary incontinence; substance tolerance, substancewithdrawal (including, substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,etc.); psychosis; schizophrenia; anxiety (including generalized anxietydisorder, panic disorder, and obsessive compulsive disorder); mooddisorders (including depression, mania, bipolar disorders); trigeminalneuralgia; hearing loss; tinnitus; neuronal damage including oculardamage; retinopathy; macular degeneration of the eye; emesis; brainedema; pain, including acute and chronic pain states, severe pain,intractable pain, inflammatory pain, neuropathic pain, post-traumaticpain, bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia), perioperative pain (general surgery, gynecological),chronic pain, neuropathic pain, post-traumatic pain, trigeminalneuralgia, migraine and migraine headache.

Potential sleep conditions or disorders for which the compounds of theinvention may be useful include enhancing sleep quality; improving sleepquality; augmenting sleep maintenance; increasing the value which iscalculated from the time that a subject sleeps divided by the time thata subject is attempting to sleep; decreasing sleep latency or onset (thetime it takes to fall asleep); decreasing difficulties in fallingasleep; increasing sleep continuity; decreasing the number of awakeningsduring sleep; decreasing nocturnal arousals; decreasing the time spentawake following the initial onset of sleep; increasing the total amountof sleep; reducing the fragmentation of sleep; altering the timing,frequency or duration of REM sleep bouts; altering the timing, frequencyor duration of slow wave (i.e. stages 3 or 4) sleep bouts; increasingthe amount and percentage of stage 2 sleep; promoting slow wave sleep;enhancing EEG-delta activity during sleep; increasing daytime alertness;reducing daytime drowsiness; treating or reducing excessive daytimesleepiness; insomnia; hypersomnia; narcolepsy; interrupted sleep; sleepapnea; wakefulness; nocturnal myoclonus; REM sleep interruptions;jet-lag; shift workers' sleep disturbances; dyssomnias; night terror;insomnias associated with depression, emotional/mood disorders, as wellas sleep walking and enuresis, and sleep disorders which accompanyaging; Alzheimer's sundowning; conditions associated with circadianrhythmicity as well as mental and physical disorders associated withtravel across time zones and with rotating shift-work schedules;conditions due to drugs which cause reductions in REM sleep as a sideeffect; syndromes which are manifested by non-restorative sleep andmuscle pain or sleep apnea which is associated with respiratorydisturbances during sleep; and conditions which result from a diminishedquality of sleep.

Pain disorders for which the compounds of the invention may be usefulinclude neuropathic pain (such as postherpetic neuralgia, nerve injury,the “dynias”, e.g., vulvodynia, phantom limb pain, root avulsions,painful diabetic neuropathy, painful traumatic mononeuropathy, painfulpolyneuropathy); central pain syndromes (potentially caused by virtuallyany lesion at any level of the nervous system); postsurgical painsyndromes (eg, postmastectomy syndrome, postthoracotomy syndrome, stumppain); bone and joint pain (osteoarthritis), repetitive motion pain,dental pain, cancer pain, myofascial pain (muscular injury,fibromyalgia); perioperative pain (general surgery, gynecological),chronic pain, dysmennorhea, as well as pain associated with angina, andinflammatory pain of varied origins (e.g. osteoarthritis, rheumatoidarthritis, rheumatic disease, teno-synovitis and gout), headache,migraine and cluster headache, headache, primary hyperalgesia, secondaryhyperalgesia, primary allodynia, secondary allodynia, or other paincaused by central sensitization.

The subject compounds could further be of potential use in a method forthe prevention, treatment, control, amelioration, or reduction of riskof the diseases, disorders and conditions noted herein. The dosage ofactive ingredient in the compositions of this invention may be varied,however, it is necessary that the amount of the active ingredient besuch that a suitable dosage form is obtained. The active ingredient maybe administered to subjects (animals and human) in need of suchtreatment in dosages that will provide optimal pharmaceutical efficacy.The selected dosage depends upon the desired therapeutic effect, on theroute of administration, and on the duration of the treatment. The dosewill vary from subject to subject depending upon the nature and severityof disease, the subject's weight, special diets then being followed by asubject, concurrent medication, and other factors which those skilled inthe art will recognize. It will be understood, however, that thespecific dose level and frequency of dosage for any particular patientmay be varied and will depend upon a variety of factors including theactivity of the specific compound employed, the metabolic stability andlength of action of that compound, the age, body weight, general health,sex, diet, mode and time of administration, rate of excretion, drugcombination, the severity of the particular condition, and the hostundergoing therapy.

Generally, dosage levels of between 0.0001 to 10 mg/kg of body weightdaily are administered to the subject, e.g., humans and elderly humans,to obtain effective modulation of M4 muscarinic acetylcholine receptors.The dosage range will generally be about 0.5 mg to 1.0 g per subject perday which may be administered in single or multiple doses. In oneembodiment, the dosage range will be about 0.5 mg to 500 mg per subjectper day; in another embodiment about 0.5 mg to 200 mg per subject perday; and in yet another embodiment about 5 mg to 50 mg per subject perday. Pharmaceutical compositions of the present invention may beprovided in a solid dosage formulation such as comprising about 0.5 mgto 500 mg active ingredient, or comprising about 1 mg to 250 mg activeingredient. The pharmaceutical composition may be provided in a soliddosage formulation comprising about 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50mg, 80 mg, 100 mg, 200 mg or 250 mg active ingredient. For oraladministration, the compositions may be provided in the form of tabletscontaining 1.0 to 1000 milligrams of the active ingredient, such as 1,5, 10, 15, 20, 25, 50, 75, 100, 150, 200, 250, 300, 400, 500, 600, 750,800, 900, and 1000 milligrams of the active ingredient for thesymptomatic adjustment of the dosage to the subject to be treated. Thecompounds may be administered on a regimen of 1 to 4 times per day, suchas once or twice per day. The compounds may be administered beforebedtime. For example, the compounds may be administered about 1 hourprior to bedtime, about 30 minutes prior to bedtime or immediatelybefore bedtime.

The compounds of the present invention may be used in combination withone or more other drugs in the treatment, prevention, control,amelioration, or reduction of risk of diseases or conditions for whichcompounds of the present invention or the other drugs may have utility,where the combination of the drugs together are safer or more effectivethan either drug alone. Such other drug(s) may be administered, by aroute and in an amount commonly used therefor, contemporaneously orsequentially with a compound of the present invention. When a compoundof the present invention is used contemporaneously with one or moreother drugs, a pharmaceutical composition in unit dosage form containingsuch other drugs and the compound of the present invention iscontemplated. However, the combination therapy may also includetherapies in which the compound of the present invention and one or moreother drugs are administered on different overlapping schedules. It isalso contemplated that when used in combination with one or more otheractive ingredients, the compounds of the present invention and the otheractive ingredients may be used in lower doses than when each is usedsingly. Accordingly, the pharmaceutical compositions of the presentinvention include those that contain one or more other activeingredients, in addition to a compound of the present invention. Theabove combinations include combinations of a compound of the presentinvention not only with one other active compound, but also with two ormore other active compounds.

Likewise, compounds of the present invention may be used in combinationwith other drugs that are used in the prevention, treatment, control,amelioration, or reduction of risk of the diseases or conditions forwhich compounds of the present invention are useful. Such other drugsmay be administered, by a route and in an amount commonly used therefor,contemporaneously or sequentially with a compound of the presentinvention. When a compound of the present invention is usedcontemporaneously with one or more other drugs, a pharmaceuticalcomposition containing such other drugs in addition to the compound ofthe present invention is contemplated. Accordingly, the pharmaceuticalcompositions of the present invention include those that also containone or more other active ingredients, in addition to a compound of thepresent invention.

The weight ratio of the compound of the present invention to the secondactive ingredient may be varied and will depend upon the effective doseof each ingredient. Generally, an effective dose of each will be used.Thus, for example, when a compound of the present invention is combinedwith another agent, the weight ratio of the compound of the presentinvention to the other agent will generally range from about 1000:1 toabout 1:1000, such as about 200:1 to about 1:200. Combinations of acompound of the present invention and other active ingredients willgenerally also be within the aforementioned range, but in each case, aneffective dose of each active ingredient should be used. In suchcombinations the compound of the present invention and other activeagents may be administered separately or in conjunction. In addition,the administration of one element may be prior to, concurrent to, orsubsequent to the administration of other agent(s).

The compounds of the present invention may be used in combination withone or more other drugs in the treatment of diseases or conditions forwhich the compounds of the present invention have utility, where thecombination of the drugs together are safer or more effective thaneither drug alone. In a embodiment, the subject compound may be employedin combination with other compounds which are known in the art, eitheradministered separately or in the same pharmaceutical compositions,including, but are not limited to: anti-Alzheimer's agents;beta-secretase inhibitors, such as verubecestat; alpha 7 nicotinicagonists, such as ABT089, SSR180711 and MEM63908; HT2a modulators, suchas pimavaserin; ADAM 10 ligands or activators; gamma-secretaseinhibitors, such as LY450139 and TAK 070; gamma-secretase inhibitors;gamma secretase modulators; tau phosphorylation inhibitors; glycinetransport inhibitors; LXR β agonists; ApoE4 conformational modulators;NR2B antagonists; androgen receptor modulators; blockers of Aβ oligomerformation; 5-HT4 agonists, such as PRX-03140; 5-HT6 antagonists, such asGSK 742467, SGS-518, FK-962, SL-65.0155, SRA-333 and xaliproden; 5-HTlaantagonists, such as lecozotan; p25/CDK5 inhibitors; NK1/NK3 receptorantagonists; COX-2 inhibitors; HMG-CoA reductase inhibitors; NSAID'sincluding ibuprofen; vitamin E; anti-amyloid antibodies (includinganti-amyloid humanized monoclonal antibodies), such as bapineuzumab,ACC001, CAD106, AZD3102, H12A11V1; anti-inflammatory compounds such as(R)-flurbiprofen, nitroflurbiprofen, ND-1251, VP-025, HT-0712 andEHT-202; PPAR gamma agonists, such as pioglitazone and rosiglitazone;CB-1 receptor antagonists or CB-1 receptor inverse agonists, such asAVE1625; antibiotics such as doxycycline and rifampin; CB-1 receptorantagonists or CB-1 receptor inverse agonists; antibiotics such asdoxycycline and rifampin; N-methyl-D-aspartate (NMDA) receptorantagonists, such as memantine, neramexane and EVT101; recombinantgrowth hormone; growth hormone secretagogues such as ibutamoren,ibutamoren mesylate, and capromorelin; histamine H₃ receptor antagonistssuch as ABT-834, ABT 829, GSK 189254 and CEP16795; AMPA agonists or AMPAmodulators, such as CX-717, LY 451395, LY404187 and S-18986; neuronalnicotinic agonists; muscarinic antagonists (e.g., M1 agonists (such asacetylcholine, oxotremorine, carbachol, or McNa343), or M₂ antagonists(such as atropine, dicycloverine, tolterodine, oxybutynin, ipratropium,methoctramine, tripitamine, or gallamine)); cholinesterase inhibitors(e.g., acetyl- and/or butyrylchlolinesterase inhibitors such asdonepezil (Aricept®,(±)-2,3-dihydro-5,6-dimethoxy-2-[[1-(phenylmethyl)-4-piperidinyl]methyl]-1H-inden-1-onehydrochloride), tacrine, phenserine, ladostigil, ABT-089, galantamine(Razadyne®), and rivastigimine (Exelon®); N-methyl-D-aspartate receptorantagonists (e.g., Namenda® (memantine HCl, available from ForrestPharmaceuticals, Inc.); combinations of cholinesterase inhibitors andN-methyl-D-aspartate receptor antagonists; anti-inflammatory agents thatcan reduce neuroinflammation; glycogen synthase kinase beta inhibitors;promoters of alpha secretase activity; PDE IV inhibitors, includingMEM1414, HT0712 and AVE8112; PDE-10 inhibitors; Tau kinase inhibitors(e.g., GSK3beta inhibitors, cdk5 inhibitors, or ERK inhibitors); GSK3βinhibitors, including AZD1080, SAR502250 and CEP16805; neuronalnicotinic agonists; selective M1 agonists; HDAC inhibitors; andmicrotubule affinity regulating kinase (MARK) ligands; Tau aggregationinhibitors (e.g., Rember®); RAGE inhibitors (e.g., TTP 488(PF-4494700)); anti-Abeta vaccine; APP ligands; agents that upregulateinsulin, cholesterol lowering agents such as HMG-CoA reductaseinhibitors (for example, statins such as Atorvastatin, Fluvastatin,Lovastatin, Mevastatin, Pitavastatin, Pravastatin, Rosuvastatin,Simvastatin) and/or cholesterol absorption inhibitors (such asEzetimibe), or combinations of HMG-CoA reductase inhibitors andcholesterol absorption inhibitors (such as, for example, Vytorin®);fibrates (such as, for example, clofibrate, Clofibride, Etofibrate, andAluminium Clofibrate); combinations of fibrates and cholesterol loweringagents and/or cholesterol absorption inhibitors; nicotinic receptoragonists; niacin; combinations of niacin and cholesterol absorptioninhibitors and/or cholesterol lowering agents (e.g., Simcor®(niacin/simvastatin, available from Abbott Laboratories, Inc.); LXRagonists; LRP mimics; H3 receptor antagonists; histone deacetylaseinhibitors; hsp90 inhibitors; 5-HT4 agonists (e.g., PRX-03140 (EpixPharmaceuticals)); 5-HT6 receptor antagonists; mGluR1 receptormodulators or antagonists; mGluR5 receptor modulators or antagonists;mGluR2/3 antagonists; Prostaglandin EP2 receptor antagonists; PAI-1inhibitors; agents that can induce Abeta efflux such as gelsolin;Metal-protein attenuating compound (e.g, PBT2); and GPR3 modulators; andantihistamines such as Dimebolin (e.g., Dimebon®, Pfizer); or otherdrugs that affect receptors or enzymes that either increase theefficacy, safety, convenience, or reduce unwanted side effects ortoxicity of the compounds of the present invention.

Examples of combinations of the compounds include combinations withagents for the treatment of schizophrenia, for example in combinationwith sedatives, hypnotics, anxiolytics, antipsychotics, antianxietyagents, cyclopyrrolones, imidazopyridines, pyrazolopyrimidines, minortranquilizers, melatonin agonists and antagonists, melatonergic agents,benzodiazepines, barbiturates, 5HT-2 antagonists, and the like, such as:adinazolam, allobarbital, alonimid, aiprazolam, amisulpride,amitriptyline, amobarbital, amoxapine, aripiprazole, bentazepam,benzoctamine, brotizolam, bupropion, busprione, butabarbital,butalbital, capuride, carbocloral, chloral betaine, chloral hydrate,clomipramine, clonazepam, cloperidone, clorazepate, chlordiazepoxide,clorethate, chlorpromazine, clozapine, cyprazepam, desipramine,dexclamol, diazepam, dichloralphenazone, divalproex, diphenhydramine,doxepin, estazolam, ethchlorvynol, etomidate, fenobam, flunitrazepam,flupentixol, fluphenazine, flurazepam, fluvoxamine, fluoxetine,fosazepam, glutethimide, halazepam, haloperidol, hydroxyzine,imipramine, lithium, lorazepam, lormetazepam, maprotiline, mecloqualone,melatonin, mephobarbital, meprobamate, methaqualone, midaflur,midazolam, nefazodone, nisobamate, nitrazepam, nortriptyline,olanzapine, oxazepam, paraldehyde, paroxetine, pentobarbital, perlapine,perphenazine, phenelzine, phenobarbital, prazepam, promethazine,propofol, protriptyline, quazepam, quetiapine, reclazepam, risperidone,roletamide, secobarbital, sertraline, suproelone, temazepam,thioridazine, thiothixene, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon,ziprasidone, zolazepam, zolpidem, and salts thereof, and combinationsthereof, and the like, or the subject compound may be administered inconjunction with the use of physical methods such as with light therapyor electrical stimulation.

In another embodiment, the subject compound may be employed incombination with levodopa (with or without a selective extracerebraldecarboxylase inhibitor such as carbidopa or benserazide),anticholinergics such as biperiden (optionally as its hydrochloride orlactate salt) and trihexyphenidyl (benzhexol) hydrochloride, COMTinhibitors such as entacapone, MOA-B inhibitors, antioxidants, A2aadenosine receptor antagonists, cholinergic agonists, NMDA receptorantagonists, serotonin receptor antagonists and dopamine receptoragonists such as alentemol, bromocriptine, fenoldopam, lisuride,naxagolide, pergolide and pramipexole. It will be appreciated that thedopamine agonist may be in the form of a pharmaceutically acceptablesalt, for example, alentemol hydrobromide, bromocriptine mesylate,fenoldopam mesylate, naxagolide hydrochloride and pergolide mesylate.

In another embodiment, the subject compound may be employed incombination with a compound from the phenothiazine, thioxanthene,heterocyclic dibenzazepine, butyrophenone, diphenylbutylpiperidine andindolone classes of neuroleptic agent. Suitable examples ofphenothiazines include chlorpromazine, mesoridazine, thioridazine,acetophenazine, fluphenazine, perphenazine and trifluoperazine. Suitableexamples of thioxanthenes include chlorprothixene and thiothixene. Anexample of a dibenzazepine is clozapine. An example of a butyrophenoneis haloperidol. An example of a diphenylbutylpiperidine is pimozide. Anexample of an indolone is molindolone. Other neuroleptic agents includeloxapine, sulpiride and risperidone. It will be appreciated that theneuroleptic agents when used in combination with the subject compoundmay be in the form of a pharmaceutically acceptable salt, for example,chlorpromazine hydrochloride, mesoridazine besylate, thioridazinehydrochloride, acetophenazine maleate, fluphenazine hydrochloride,flurphenazine enathate, fluphenazine decanoate, trifluoperazinehydrochloride, thiothixene hydrochloride, haloperidol decanoate,loxapine succinate and molindone hydrochloride. Perphenazine,chlorprothixene, clozapine, haloperidol, pimozide and risperidone arecommonly used in a non-salt form. Thus, the subject compound may beemployed in combination with acetophenazine, alentemol, aripiprazole,amisuipride, benzhexol, bromocriptine, biperiden, chlorpromazine,chlorprothixene, clozapine, diazepam, fenoldopam, fluphenazine,haloperidol, levodopa, levodopa with benserazide, levodopa withcarbidopa, lisuride, loxapine, mesoridazine, molindolone, naxagolide,olanzapine, pergolide, perphenazine, pimozide, pramipexole, quetiapine,risperidone, sulpiride, tetrabenazine, frihexyphenidyl, thioridazine,thiothixene, trifluoperazine or ziprasidone.

Examples of combinations of the compounds include combinations withagents for the treatment of pain, for example non-steroidalanti-inflammatory agents, such as aspirin, diclofenac, duflunisal,fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen,ketorolac, naproxen, oxaprozin, piroxicam, sulindac and tolmetin; COX-2inhibitors, such as celecoxib, rofecoxib, valdecoxib, 406381 and 644784;CB-2 agonists, such as 842166 and SAB378; VR-1 antagonists, such asAMG517, 705498, 782443, PAC20030, V114380 and A425619; bradykinin B1receptor antagonists, such as SSR240612 and NVPSAA164; sodium channelblockers and antagonists, such as VX409 and SPI860; nitric oxidesynthase (NOS) inhibitors (including iNOS and nNOS inhibitors), such asSD6010 and 274150; glycine site antagonists, including lacosamide;neuronal nicotinic agonists, such as ABT 894; NMDA antagonists, such asAZD4282; potassium channel openers; AMPA/kainate receptor antagonists;calcium channel blockers, such as ziconotide and NMED160; GABA-Areceptor IO modulators (e.g., a GABA-A receptor agonist); matrixmetalloprotease (MMP) inhibitors; thrombolytic agents; opioid analgesicssuch as codeine, fentanyl, hydromorphone, levorphanol, meperidine,methadone, morphine, oxycodone, oxymorphone, pentazocine, propoxyphene;neutrophil inhibitory factor (NIF); pramipexole, ropinirole;anticholinergics; amantadine; monoamine oxidase B15 (“MAO-B”)inhibitors; 5HT receptor agonists or antagonists; mGlu5 antagonists,such as AZD9272; alpha agonists, such as AGNXX/YY; neuronal nicotinicagonists, such as ABT894; NMDA receptor agonists or antagonists, such asAZD4282; NKI antagonists; selective serotonin reuptake inhibitors(“SSRI”) and/or selective serotonin and norepinephrine reuptakeinhibitors (“SSNRI”), such as duloxetine; tricyclic antidepressantdrugs, norepinephrine modulators; lithium; valproate; gabapentin;pregabalin; rizatriptan; zolmitriptan; naratriptan and sumatriptan.

The compounds of the present invention may be administered incombination with compounds useful for enhancing sleep quality andpreventing and treating sleep disorders and sleep disturbances,including e.g., sedatives, hypnotics, anxiolytics, antipsychotics,antianxiety agents, antihistamines, benzodiazepines, barbiturates,cyclopyrrolones, orexin antagonists, alpha-1 antagonists, GABA agonists,5HT-2 antagonists including 5HT-2A antagonists and 5HT-2A/2Cantagonists, histamine antagonists including histamine H3 antagonists,histamine H3 inverse agonists, imidazopyridines, minor tranquilizers,melatonin agonists and antagonists, melatonergic agents, orexinantagonists, orexin agonists, prokineticin agonists and antagonists,pyrazolopyrimidines, T-type calcium channel antagonists,triazolopyridines, and the like, such as: adinazolam, allobarbital,alonimid, alprazolam, amitriptyline, amobarbital, amoxapine,armodafinil, APD-125, bentazepam, benzoctamine, brotizolam, bupropion,busprione, butabarbital, butalbital, capromorelin, capuride,carbocloral, chloral betaine, chloral hydrate, chlordiazepoxide,clomipramine, clonazepam, cloperidone, clorazepate, clorethate,clozapine, conazepam, cyprazepam, desipramine, dexclamol, diazepam,dichloralphenazone, divalproex, diphenhydramine, doxepin, EMD-281014,eplivanserin, estazolam, eszopiclone, ethchlorynol, etomidate, fenobam,filorexant, flunitrazepam, flurazepam, fluvoxamine, fluoxetine,fosazepam, gaboxadol, glutethimide, halazepam, hydroxyzine, ibutamoren,imipramine, indiplon, lithium, lorazepam, lormetazepam, LY-156735,maprotiline, MDL-100907, mecloqualone, melatonin, mephobarbital,meprobamate, methaqualone, methyprylon, midaflur, midazolam, modafinil,nefazodone, NGD-2-73, nisobamate, nitrazepam, nortriptyline, oxazepam,paraldehyde, paroxetine, pentobarbital, perlapine, perphenazine,phenelzine, phenobarbital, prazepam, promethazine, propofol,protriptyline, quazepam, ramelteon, reclazepam, roletamide,secobarbital, sertraline, suproclone, suvorexant, TAK-375, temazepam,thioridazine, tiagabine, tracazolate, tranylcypromaine, trazodone,triazolam, trepipam, tricetamide, triclofos, trifluoperazine,trimetozine, trimipramine, uldazepam, venlafaxine, zaleplon, zolazepam,zopiclone, zolpidem, and salts thereof, and combinations thereof, andthe like, or the compound of the present invention may be administeredin conjunction with the use of physical methods such as with lighttherapy or electrical stimulation.

The compounds of the present invention may be administered by oral,parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV,intracisternal injection or infusion, subcutaneous injection, orimplant), by inhalation spray, nasal, vaginal, rectal, sublingual, ortopical routes of administration and may be formulated, alone ortogether, in suitable dosage unit formulations containing conventionalnon-toxic pharmaceutically acceptable carriers, adjuvants and vehiclesappropriate for each route of administration. The subject or patient towhom the compounds of the present invention is administered is generallya human being, male or female, but may also encompass other mammals,such as dogs, cats, mice, rats, cattle, horses, sheep, rabbits, monkeys,chimpanzees or other apes or primates, for which treatment of the abovenoted disorders is desired.

The pharmaceutical compositions for the administration of the compoundsof this invention may conveniently be presented in dosage unit form andmay be prepared by any of the methods well known in the art of pharmacy.All methods include the step of bringing the active ingredient intoassociation with the carrier which constitutes one or more accessoryingredients. In general, the pharmaceutical compositions are prepared byuniformly and intimately bringing the active ingredient into associationwith a liquid carrier or a finely divided solid carrier or both, andthen, if necessary, shaping the product into the desired formulation. Inthe pharmaceutical composition the active object compound is included inan amount sufficient to produce the desired effect upon the process orcondition of diseases. As used herein, the term “composition” isintended to encompass a product comprising the specified ingredients inthe specified amounts, as well as any product which results, directly orindirectly, from combination of the specified ingredients in thespecified amounts.

Pharmaceutical compositions intended for oral use may be preparedaccording to any method known to the art for the manufacture ofpharmaceutical compositions and such compositions may contain one ormore agents selected from the group consisting of sweetening agents,flavoring agents, coloring agents and preserving agents in order toprovide pharmaceutically elegant and palatable preparations. Tabletscontain the active ingredient in admixture with non-toxicpharmaceutically acceptable excipients which are suitable for themanufacture of tablets. These excipients may be for example, inertdiluents, such as calcium carbonate, sodium carbonate, lactose, calciumphosphate or sodium phosphate; granulating and disintegrating agents,for example, corn starch, or alginic acid; binding agents, for examplestarch, gelatin or acacia, and lubricating agents, for example magnesiumstearate, stearic acid or talc. The tablets may be uncoated or they maybe coated by known techniques to delay disintegration and absorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. Compositions for oral use may also be presented as hardgelatin capsules wherein the active ingredient is mixed with an inertsolid diluent, for example, calcium carbonate, calcium phosphate orkaolin, or as soft gelatin capsules wherein the active ingredient ismixed with water or an oil medium, for example peanut oil, liquidparaffin, or olive oil. Aqueous suspensions contain the active materialsin admixture with excipients suitable for the manufacture of aqueoussuspensions. Oily suspensions may be formulated by suspending the activeingredient in a suitable oil. Oil-in-water emulsions may also beemployed. Dispersible powders and granules suitable for preparation ofan aqueous suspension by the addition of water provide the activeingredient in admixture with a dispersing or wetting agent, suspendingagent and one or more preservatives. Pharmaceutical compositions of thepresent compounds may be in the form of a sterile injectable aqueous oroleagenous suspension. Pharmaceutical compositions of the presentcompounds in the form of a sterile injectable aqueous or oleagenoussuspension may be formulated by known techniques for depo administrationand thereby provide a sustained action over a longer period. Thecompounds of the present invention may also be administered in the formof suppositories for rectal administration. For topical use, creams,ointments, jellies, solutions or suspensions, etc., containing thecompounds of the present invention may be employed. The compounds of thepresent invention may also be formulated for administered by inhalation.The compounds of the present invention may also be administered by atransdermal patch by methods known in the art.

Several methods for preparing the compounds of this invention areillustrated in the following Schemes and Examples. Starting materialsare made according to procedures known in the art or as illustratedherein. The following abbreviations are used herein: Me: methyl; Et:ethyl; t-Bu: tert-butyl; Ar: aryl; Ph: phenyl; aq: aqueous; BINAP:2,2′-bis(diphenylphosphino)-1,1′-binaphthyl; Bn: benzyl; Ac: acetyl;Boc: tert-butyloxy carbonyl; BSA: bovine serum albumin; CAN:acetonitrile; Cbz: carboxylbenzyl; CbzCl: benzylchloroformate; CDI:carbonyl diimidazole; DAST: diethylaminosulfur trifluoride; DCM:dichloromethane; DCE: dichloroethane; DEA: diethylamine; DEAD:diethylazodicarboxylate; DIAD: diisopropyl azodicarboxylate; DIBAL:diisobutylaluminium hydride; DIPEA: N,N-diisopropylethylamine; DMAP:4-dimethylaminopyridine; DMF: N,N-dimethylformamide; DMS:dimethylsulfide; DMSO: dimethylsulfoxide; dppf:1,1′-bis(diphenyl-phosphino)ferrocene; CH2Cl2: dichloromethane; EDC:N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide; Et3N: triethylamine;EtOAc: ethyl acetate; EtOH: ethanol; HATU:(1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate); HCl: hydrogen chloride; HOAt:1-hydroxy-7-aza-benzotriazole; HOBT: hydroxybenzotriazole hydrate; HPLC:high performance liquid chromatography; Hunig's base:N,N-diisopropylethylamine; LDA: diisopropylamine; LHMDS: lithiumbis(trimethylsilyl)amide; mCPBA: meta-chloroperbenzoic acid; MeOH:methanol; MgSO4: magnesium sulfate; Ms: methanesulfonyl; MTBE: methyltert-butyl ether; MS: Mass spectra; NaHCO3: sodium bicarbonate; NaOH:sodium hydroxide; NBS: N-bromosuccinimide; NCS: N-chlorosuccinimide;NMM: N-methylmorpholine; NMR: nuclear magnetic resonance; PtO2: platinumoxide; PyClu: 1-(chloro-1-pyrrolidinylmethylene)-pyrrolidiniumhexafluorophosphate; rt: room temperature; SEM:2-(Trimethylsilyl)ethoxy]methyl; SFC: supercritical fluidchromatography; SOCl2: thionyl chloride; T3P:2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide; TBAF:tetra-n-butylammonium fluoride; TBS: tert-Butyldimethylsilyl; TEA:triethylamine; TES: Triethylsilyl; TFA: trifluoracetic acid; Tf:triflate; TFAA: trifluoroacetic anhydride; THF: tetrahydrofuran; TIPS:tri-isopropylsilyl; TLC: thin layer chromatography; Ts: toluenesulfonyl;X-Phos: 2-(dicyclohexyl-phosphino)-2′,4′,6′-triisopropyl-biphenyl.

The compounds of the present invention can be prepared in a variety offashions. In some cases the final product may be further modified, forexample, by manipulation of substituents. These manipulations mayinclude, but are not limited to, reduction, oxidation, alkylation,acylation, and hydrolysis reactions which are commonly known to thoseskilled in the art. In some cases the order of carrying out theforegoing reaction schemes may be varied to facilitate the reaction orto avoid unwanted reaction products. Because the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used herein is well within the skill of aperson versed in the art. The following examples are provided so thatthe invention might be more fully understood. These examples areillustrative only and should not be construed as limiting the inventionin any way. Absolute stereochemistry of separate stereoisomers in theexamples and intermediates are not determined unless stated otherwise inan example or explicitly in the nomenclature.

Intermediate A is prepared according to Scheme A via condensation ofcommercially available hydroxynitrile A-1 with oxalyl chloride to yieldadduct A-2. A Finkelstein reaction of chloride A-2 with sodium iodide,catalyzed by camphorsulfonic acid (CSA), results in iodide product A-3.A hetero-Diels-Alder reaction of diene A-3 with a commercially availableynone gives pyridine A-4. A subsequent copper-meditated cyanationprovides intermediate A.

Intermediate A1

Methyl 6-chloro-2-cyano-5-methylnicotinate (Scheme A) Step 1:3,5-Dichloro-6-methyl-2H-1,4-oxazin-2-one

Into a 10-L 4-necked round-bottom flask was charged oxalic dichloride(3.32 kg, 26.2 mol) and chlorobenzene (3.5 L) under an inert atmosphereof nitrogen. A solution of 2-hydroxypropanenitrile (464.8 g, 6.54 mol)in chlorobenzene (500 mL) was added dropwise to the flask at 0° C. Thesystem was heated to 90° C. and triethylamine hydrochloride (66.2 g, 481mmol) was added in portions at 90° C. The resulting solution was stirredfor 3 h before concentrating the mixture under reduced pressure. Theresulting solution was diluted with ether (5 L) and the solids werefiltered out. The filtrate concentrated and was then applied purified bysilica gel column chromatography (0:1-1:4 ethyl acetate:petroleum ether)to yield the title compound.

Step 2: 5-Chloro-3-iodo-6-methyl-2H-1,4-oxazin-2-one

Into a 10-L 4-necked round-bottom flask was added3,5-dichloro-6-methyl-2H-1,4-oxazin-2-one (470.8 g, 2.62 mol), acetone(10 L), NaI (1568 g, 10.5 mol) and camphorsulfonic acid (40 g, 172.2mmol) under an atmosphere of nitrogen. The resulting solution wasstirred for 3 h at 25° C. The mixture was concentrated and then dilutedwith water (20 L) and dichloromethane (3×5 L). The organic layers werecombined and washed with brine (5 L). The mixture was dried overanhydrous sodium sulfate, filtered and was concentrated under reducedpressure to yield the title compound.

Step 3: Methyl 6-chloro-2-iodo-5-methylnicotinate

Into a 5-L 3-necked round-bottom flask was placed5-chloro-3-iodo-6-methyl-2H-1,4-oxazin-2-one (638 g, 2.35 mol), toluene(2.3 L), and methyl prop-2-ynoate (592.8 g, 7.05 mol) under anatmosphere of nitrogen. The resulting solution was stirred for 2 days at80° C. The reaction was cooled and the volatiles were removed underreduced pressure. The residue was purified by silica gel columnchromatography (0:1-1:50 ethyl acetate:petroleum ether) to provide themajor regioisomeric product as the title compound.

Step 4: Methyl 6-chloro-2-cyano-5-methylnicotinate

Into a 20-mL microwave tube was added methyl6-chloro-2-iodo-5-methylpyridine-3-carboxylate (2 g, 6.42 mmol), DMF (15mL), and CuCN (850 mg, 9.60 mmol). The resulting solution was stirredfor 5 min at 100° C. by microwave irradiation. The mixture was dilutedwith water (20 mL) and a saturated, aqueous solution of NH₄Cl (100 mL).Dichloromethane (2×20 mL) was used to extract the crude material and theorganic layers were combined and dried over anhydrous sodium sulfate.The residue was purified by silica gel chromatography (0:1-1:8 ethylacetate:petroleum ether) to provide the title compound. MS: 211 (M+1).¹H NMR (500 MHz, CDCl₃): δ 7.87 (s, 1H), 3.95 (s, 4H), 2.37 (s, 3H).

The following intermediates in table A were prepared according to schemeA using the procedure outlined in the synthesis of intermediate A1 usingcommercially available hydroxynitriles in step 1 and using commerciallyavailable ynones for step 3.

TABLE A Inter- MS mediate Structure Name (M + 1) A2

dimethyl 6-chloro- 2-cyano-5- methylpyridine- 3,4-dicarboxylate 269 A3

methyl 6-chloro- 2-cyano-5- ethylnicotinate 225 A4

dimethyl 2-chloro- 6-cyanopyridine- 3,5-dicarboxylate 356 A5

methyl 6-chloro- 2-cyano-4,5- dimethylnicotinate 225

An alternative method to the described procedure outlined in thesynthesis of intermediate A is shown in Scheme AB. Intermediate AB issynthesized beginning from a condensation of 2-cyanoacetamide and β-ketoester AB-2 to form pyridone AB-3. Reaction with phosphoryl chlorideprovides pyridine AB-4, which is then tranformed in 2-steps to esterAB-6 via intermediate acid AB-5. Cyanation via reaction with copper(I)cyanide provides intermediate AB.

Intermediate AB

Methyl 6-chloro-2-cyano-4,5-dimethylnicotinate (Scheme AB) Step 1:6-Hydroxy-4,5-dimethyl-2-oxo-1,2-dihydropyridine-3-carbonitrile

To a solution of 2-cyanoacetamide (100 g, 1.2 mol) was dissolved in MeOH(1.5 L), was added ethyl 2-methyl-3-oxobutanoate (171 g, 1.2 mol) andpotassium hydroxide (100 g, 1.8 mol). The resulting solution was stirredfor 4 h at 65° C. before being cooled to 10° C. The solids werecollected by filtration and were dissolved in 2 L of hot water (70° C.).The mixture was filtered and the filtrate was adjusted to pH˜1 withaqueous hydrogen chloride (6 N). The solids were collected by filtrationto yield the title compound.

Step 2: 2,6-Dichloro-4,5-dimethylpyridine-3-carbonitrile

To phosphoroyl trichloride (126 mL) was added2,6-dihydroxy-4,5-dimethylpyridine-3-carbonitrile (70 g, 426.41 mmol) inseveral batches. The system was sealed and the resulting solution wasstirred for 6 h at 180° C. The reaction was cooled to RT and the mixturewas poured into ice water (500 mL). The solids were collected byfiltration to afford the title compound.

Step 3: 2,6-Dichloro-4,5-dimethylpyridine-3-carboxylic Acid

2,6-Dichloro-4,5-dimethylpyridine-3-carbonitrile (100 g, 497.4 mmol) wasdissolved in sulfuric acid (250 mL). Nitric acid (75 mL) was addeddropwise at 110-150° C. over the course of 1 h and the resultingsolution was stirred 110° C. for 1 h. The reaction was then poured intoice water (1 L) and the solids were collected by filtration. Thematerial was then dissolved in EtOAc (200 mL), dried over anhydroussodium sulfate and concentrated under reduced pressure to afford thetitle compound.

Step 4: Methyl 2,6-dichloro-4,5-dimethylpyridine-3-carboxylate

To a solution of 2,6-dichloro-4,5-dimethylpyridine-3-carboxylic acid(100 g, 454.4 mmol) in DMF (1.5 L) was added potassium carbonate (95 g,682.4 mmol), iodomethane (129 g, 908.8 mmol). The resulting mixture wasstirred for 1 h at RT before the reaction was quenched by the additionof ice water (1.5 L). The crude reaction was extracted with EtOAc (1L×3), dried over anhydrous sodium sulfate and concentrated under reducedpressure. The residue was purified by silica gel chromatography (1/10EtOAc/petroleum ether) to afford the title compound.

Step 5: Methyl 6-chloro-2-cyano-4,5-dimethylpyridine-3-carboxylate

A solution of methyl 2,6-dichloro-4,5-dimethylpyridine-3-carboxylate (1g, 4.27 mmol) in NMP (5 mL) and copper(I) cyanide (570 mg, 6.36 mmol)was stirred for 2 h at 180° C. under an nitrogen atmosphere. Aftercooling to RT, the reaction mixture was poured into ice water and wasextracted with EtOAc. The solids were filtered out and the filtrate wasfurhter extraced with EtOAc (3×) and the combined organic phases weredried over anhydrous sodium sulfate and concentrated. The crude materalwas purified by reverse phase HPLC (30-60% MeCN/water with 1% NH₄HCO₃modifier) and then again by SFC (EnantioPak-A1 column, 20%/80% MeOH/CO₂)to afford the title copmound. ¹H NMR (400 MHz, CD₃OD): δ 4.01 (s, 3H),2.51 (s, 3H), 2.48 (s, 3H).

Intermediate B is prepared according to Scheme B in a two-step processfrom intermediate A via a platinum-mediated nitrile reduction andsubsequent base-mediated cyclization of amine B-1.

Intermediate B1

2-Chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (Scheme B)Step 1: Methyl 2-(aminomethyl)-6-chloro-5-methylnicotinate hydrochloride

Into a 5-L 2-necked round-bottom flask was placed methyl6-chloro-2-cyano-5-methylpyridine-3-carboxylate (intermediate A1, 82 g,389.3 mmol), 3:1 ethanol:chloroform (2.5 L) and PtO₂ (15 g). Theresulting solution was stirred for 36 h at RT under an atmosphere ofhydrogen. The solids were removed by filtration and the filtrate wasconcentrated under reduced pressure to yield the title compound.

Step 2: 2-Chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Into a 10-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen, was placed methyl2-(aminomethyl)-6-chloro-5-methylpyridine-3-carboxylate hydrochloride(110 g, 438.06 mmol), methanol (6 L), TEA (221.6 g, 2.19 mol). Theresulting solution was stirred for 12 h at RT. The solids were removedby filtration and the filtrate was concentrated under reduced pressureto yield the crude product. Addition of hot DCM eventually resulted inthe formation of a precipitate which was isolated by filtration to yieldthe title compound. MS: 183 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 2.45 (s,3H), 4.39 (s, 2H), 8.11 (s, 1H), 8.82 (s, 1H).

The following intermediates in table B were prepared according to schemeB using the procedure outlined in the synthesis of intermediate B1.

TABLE B MS Intermediate Structure Name (M + 1) B2

2-chloro-3-ethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 197

Intermediate C is prepared from protected piperidone C-1 which wasconverted to the enol silane C-2 under the action of TBSOTf in thepresence of base. Electrophilic fluorination by Selectfluor® on C-2provided the corresponding alpha-fluorinated product C-3. Reduction bysodium borohydride and subsequent chiral SFC separation providedintermediate C1 and intermediate C2 as single enantiomers.

Intermediate C1 and C2

Benzyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate and benzyl(3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (Scheme C) Step 1:Benzyl4-((tert-butyldimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate

To a solution of benzyl 4-oxopiperidine-1-carboxylate (260 g, 1.11 mmol)in DMF (700 mL) and was added DIPEA (216 g, 1.67 mol) and TBSOTf (83 g,1.45 mol) at RT under an atmosphere of nitrogen. The reaction mixturewas stirred for 16 h. After diluting with water (1.5 L) and extractingwith EtOAc (1.5 L×3), the organic layers were combined and washed withbrine (2 L×3) and concentrated. The residue was purified by silica gelcolumn chromatography (50:1-20:1 petroleum ether:ethyl acetate) toobtain the title compound.

Step 2: Benzyl 3-fluoro-4-oxopiperidine-1-carboxylate

To a solution of benzyl4-((tert-butyldimethylsilyl)oxy)-3,6-dihydropyridine-1(2H)-carboxylate(200 g, 0.58 mol) in MeCN (1.6 L) was added Selectfluor® (224 g, 0.63mol) at 25° C. The reaction mixture was stirred for 10 h. The volatileswere removed under reduced pressure and the residue was diluted withEtOAc (2 L) and then washed with brine (1.5 L×3). The organic wasconcentrated in vacuo to give the title compound which was carriedforward without further purification.

Step 3: Benzyl (3S,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate andbenzyl (3R,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate

To a solution of benzyl 3-fluoro-4-oxopiperidine-1-carboxylate (300 g,1.19 mol) in MeOH (2.5 L) was added NaBH₄ (50 g, 1.31 mol) at 0° C.After stirring for 4 h at RT, the volatiles were removed under reducedpressure and the residue was diluted with EtOAc (2 L) and washed withwater (2 L) and then brine (2 L×2). The organic was concentrated invacuo and was purified on silica gel by column chromatography (10:1-2:1petroleum ether:ethyl acetate) to obtain the racemic product. Thematerial was then purified by chiral SFC (AD column, 30%/70% EtOH with0.1% ammonium hydroxide modifier/CO₂) to afford intermediate C1 (fastereluting 3S,4R isomer): MS: 254 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.41-7.29 (m, 1H), 5.15 (s, 1H), 4.74-4.52 (m, 1H), 4.11-3.76 (m, 3H),3.62-3.17 (m, 2H), 2.07 (br s, 1H), 1.93-1.70 (m, 2H). Intermediate C2(slower eluting 3R,4S isomer): MS: 254 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.40-7.30 (m, 5H), 5.15 (s, 2H), 4.75-4.51 (m, 1H), 4.09-3.69 (m, 3H),3.62-3.18 (m, 2H), 2.08 (br s, 1H), 1.93-1.71 (m, 2H).

Intermediate D is prepared from a racemic mixture of intermediate C1 andintermediate C2 which is carried through a Mitsunobu reaction withp-nitrobenzoic acid to provide trans-racemic adduct D-1. Subsequentsaponification reveals alcohol D-2. Chiral separation to resolve theenantiomers is carried out to provide intermediate D1 and intermediateD2 as single enantiomers.

Intermediate D1 and D2

Benzyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate and benzyl(3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate (Scheme D) Step 1:Benzyl trans-3-fluoro-4-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate

To a stirred solution of benzylcis-3-fluoro-4-hydroxypiperidine-1-carboxylate (60 g, 0.24 mol,intermediate C1 and C2) in THF (400 mL) was added p-nitrobenzoic acid(60 g, 0.36 mol) and Ph₃P (92 g, 0.35 mol) at RT. After cooling themixture to ˜0-5° C., DIAD (78 g, 0.39 mol) was added dropwise. Thereaction was stirred 15 h at RT and was quenched with an aqueous,saturated NH₄Cl solution (600 mL) and was then extracted with EtOAc (500mL×3). The combined organic layers were washed with brine (1 L), driedover anhydrous sodium sulfate and concentrated under reduced pressure.The residue was purified on silica gel by column chromatography (10:1petroleum ether:ethyl acetate) to yield the title compound.

Step 2: Benzyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate

To a solution of benzylcis-3-fluoro-4-((4-nitrobenzoyl)oxy)piperidine-1-carboxylate (90 g, 0.22mol) in MeOH (900 mL) was added potassium carbonate (90 g, 0.65 mol).The resulting mixture was stirred at RT for 15 h and then the volatileswere removed under reduced pressure. The residue was partitioned betweenEtOAc (200 mL) and saturated NH₄Cl (aq) (200 mL). The aqueous layer wasextracted with EtOAc (200 mL×2) and the combined organic layers werewashed with brine (500 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by silica gel columnchromatography (1:1 petroleum ether:ethyl acetate) to afford the titlecompound.

Step 3: Benzyl (3R,4R)-3-fluoro-4-hydroxypiperidine-1-carboxylate andbenzyl (3S,4S)-3-fluoro-4-hydroxypiperidine-1-carboxylate

Benzyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate was resolvedinto single enantiomers via chiral SFC (AD column, 5-40% EtOH with 0.05%diethylamine modifier/CO₂) to afford intermediate D1 (faster eluting3R,4R isomer): MS: 254 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.31-7.56 (m,5H), 5.19 (s, 2H), 4.17-4.37 (m, 2H), 3.84-3.95 (m, 2H), 3.06-3.28 (m,2H), 2.28 (s, 1H), 2.01 (s, 1H), 1.57 (s, 1H). Intermediate D2 (slowereluting 3S,4S isomer): MS: 254 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.31-7.56 (m, 5H), 5.19 (s, 2H), 4.17-4.37 (m, 2H), 3.84-3.95 (m, 2H),3.06-3.28 (m, 2H), 2.28 (s, 1H), 2.01 (s, 1H), 1.57 (s, 1H).

Intermediate E is prepared from a trans-racemate D-2. The piperidineN-protecting group was switched under reductive conditions in thepresence of Boc₂O to provide alcohol E-1. Mitsunobu reaction with acommercially available or known phenol (wherein Ar is an aromatic orheteroaromatic ring of R¹) provides the cis-racemic alcohol E-2.Deprotection of the piperidine was completed under acidic conditions toyield intermediate E. Chiral separation to resolve the enantiomers maybe carried out on either the pentultimate compound E-2 or intermediate Eto yield single enantiomer products.

Intermediate E1

3-(cis-3-Fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride (Scheme E)Step 1: tert-Butyl trans-3-fluoro-4-hydroxypiperidine-1-carboxylate

A mixture of benzyl cis-3-fluoro-4-hydroxypiperidine-1-carboxylate (40g, 0.16 mol), Boc₂O (45 g, 0.206 mol) and methanol (600 mL) was stirredin the presence of Pd(OH)₂/C under hydrogen (35 psi) at RT. Uponcompletion, the mixture was filtered and the filtrate was concentratedin vacuo. The resultant residue was purified by silica gel columnchromatography (6:1 petroleum ether:ethyl acetate) to afford the titlecompound.

Step 2: tert-Butylcis-4-(3-cyanophenoxy)-3-fluoropiperidine-1-carboxylate

To a flask with tert-butylcis-3-fluoro-4-hydroxypiperidine-1-carboxylate (25 g, 98.8 mmol) in THF(500 mL) was added PPh₃ (77.5 g, 295.8 mmol) and 3-hydroxybenzonitrile(15 g, 120 mmol) at RT. DIAD (50 mL, 257.8 mmol) was added dropwise tothe solution at 30-40° C. and the mixture was refluxed until thereaction was complete. The reaction was poured into 1 M aqueous NaOH andextracted with ethyl acetate (2×) and the organic layer was dried overanhydrous sodium sulfate and concentrated. The title compound wascarried forward without further purification.

Step 3: 3-(cis-3-Fluoropiperidin-4-yl)oxy)benzonitrile hydrochloride

To a flask with crude tert-butylcis-4-(3-cyanophenoxy)-3-fluoropiperidine-1-carboxylate in MeOH (100 mL)was added HCl (2 M in ether). The mixture was stirred at 30° C. for 2 hand the title compound was isolated by filtration. ¹H NMR (400 MHz,D₂O): δ 7.25-7.65 (m, 5H), 5.35-5.25 (m, 1H), 4.7-4.8 (m, 1H), 3.8-3.7(m, 1H), 3.5-3.1 (m, 3H), 2.25-2.1 (m, 2H).

Intermediate E2 and E3

3-(((3R,4S)-3-Fluoropiperidin-4-yl)oxy)pyridine dihydrochloride and3-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)pyridine dihydrochloride (SchemeE) Step 1:tert-Butyl-(3R,4S)-3-fluoro-4-(pyridin-3-yloxy)piperidine-1-carboxylateandtert-Butyl-(3S,4R)-3-fluoro-4-(pyridin-3-yloxy)piperidine-1-carboxylate

Into a 10-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of tert-butyltrans-3-fluoro-4-hydroxypiperidine-1-carboxylate (180 g, 821 mmol),pyridin-3-ol (117 g, 1.23 mol), and PPh₃ (323 g, 1.23 mol) in THF (4 L).This was followed by the dropwise addition of DIAD (249 g, 1.23 mol,1.50 equiv) at 0° C. After stirring for 15 h at 40° C., the resultingmixture was concentrated under reduced pressure. The residue waspurified by silica gel column chromatography (0:1-1:1 ethylacetate:petroleum ether) to yield the product. The mixture of the twostereoisomers was purified by chiral SFC (AD-H column, 1:1 MeOH with0.2% diethylamine modifier: CO₂) to afford the title compounds.

Step 1: 3-(((3R,4S)-3-Fluoropiperidin-4-yl)oxy)pyridine dihydrochlorideand 3-(((3S,4R)-3-fluoropiperidin-4-yl)oxy)pyridine dihydrochloride

Into two separate flasks was placedtert-butyl-(3R,4S)-3-fluoro-4-(pyridin-3-yloxy)piperidine-1-carboxylateandtert-butyl-(3S,4R)-3-fluoro-4-(pyridin-3-yloxy)piperidine-1-carboxylate(45 g, 151.85 mmol). To each flask was then added HCl in dioxane (4 M,500 mL) and the reactions were stirred at RT. The products werecollected by filtration to yield to afford intermediate E2 (fastereluting isomer): MS: 197 (M−2HCl+1). ¹H NMR (400 MHz, D₂O): δ 2.23-2.31(2H, s), 3.10-3.30 (1H, m), 3.40-3.60 (2H, m), 3.70-3.80 (1H, m),4.90-5.10 (1H, m), 5.20-5.40 (1H, d), 7.90-8.00 (1H, m), 8.20-8.30 (1H,m), 8.45-8.55 (1H, d), 8.60-8.70 (1H, d). Intermediate E3 (slowereluting isomer): MS: 197 (M−2HCl+1). ¹H NMR (300 MHz, D₂O): δ2.20-2.31(2H, m), 3.10-3.30 (1H, m), 3.40-3.60 (2H, m), 3.70-3.80 (1H, m),4.90-5.10 (1H, m), 5.20-5.40 (1H, d), 7.90-8.00 (1H, m), 8.20-8.30 (1H,m), 8.45-8.55 (1H, d), 8.60-8.70 (1H, d).

Intermediate F is prepared according to scheme F via Mitsunobu reactionof commericially available N-protected piperdine F-1 with known orprepared phenols (wherein Ar is an aromatic or heteroaromatic ring ofR¹) to yield adduct F-2. Subsequent deprotection of ether F-2 providesintermediate F.

Intermediate F1

2-Methoxy-5-(piperidin-4-yloxy)pyridine dihydrochloride (Scheme F) Step1: tert-Butyl 4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

Into a 5-L 4-necked round-bottom flask purged and maintained with aninert atmosphere of nitrogen was placed a solution of6-methoxypyridin-3-ol (200 g, 1.60 mol) in THF (1.5 L). tert-Butyl4-hydroxypiperidine-1-carboxylate (386 g, 1.92 mol) andtriphenylphosphine (545 g, 2.08 mol) were added followed by the dropwiseaddition of DIAD (420 g, 2.08 mol) at RT. After stirring for 1 h at 40°C., the resulting solution was diluted with water (2 L) and waspartitioned with EtOAc (4 L). The organic layers were combined, washedwith brine (2 L), dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by silica gel columnchromatography (1/10 ethyl acetate/petroleum ether) to yield the titlecompound.

Step 2: 2-Methoxy-5-(piperidin-4-yloxy)pyridine dihydrochloride

A solution of tert-butyl4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate (270 g, 875.6mmol) in methanol (2 L) was bubbled slowly with HCl (g). The resultingsolution was stirred for 2 h at RT. The volatiles were removed and thecrude material was diluted with hot EtOAc:MeOH (8:1) and was then cooledto obtain a precipitate that was collected by filtration to yield thetitle compound. MS: 236 (M−2HCl+H). ¹H NMR (300 MHz, D₂O): δ 7.79-7.98(m, 2H), 7.24-7.23 (m, 1H), 4.0 (s, 3H), 3.36-3.40 (m, 2H), 3.15-3.26(m, 2H), 1.97-2.14 (m, 4H).

Intermediate F2

5-(((3R,4R)-3-Fluoropiperidin-4-yl)oxy)-2-methoxypyridine (Scheme F)Step 1: Benzyl(3R,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate

To a flask with triphenylphosphine (1.204 g, 4.59 mmol) in toluene (4.5mL) was added di-tert-butyl azodicarboxylate (0.916 g, 3.98 mmol) at 0°C. The reaction was warmed to RT and was stirred for 20 min before theaddition of (3R,4S)-benzyl 3-fluoro-4-hydroxypiperidine-1-carboxylate(0.775 g, 3.06 mmol, intermediate C2) and 6-methoxypyridin-3-ol (0.383g, 3.06 mmol) in a solution of toluene (4.5 mL). The reaction mixturewas sonicated then heated to 80° C. for 16 h. The volatiles were removedunder reduced pressure and the residue was dissolved in EtOAc. Theorganic layer was washed with aqueous 1 M NaOH (2×), water (2×) andbrine before being dried over anhydrous sodium sulfate and concentratedunder reduced pressure. The residue was purified by silica gel columnchromatography (0-30% EtOAc in hexanes) to yield the title compound.

Step 2: 5-(((3R,4R)-3-Fluoropiperidin-4-yl)oxy)-2-methoxypyridine

A solution of benzyl(3R,4R)-3-fluoro-4-((6-methoxypyridin-3-yl)oxy)piperidine-1-carboxylate(1.04 g, 2.89 mmol) in methanol (20 mL) was prepared under an atmosphereof nitrogen. Pearlman's catalyst (20 wt %, 0.203 g, 0.289 mmol) wasadded and the system was degassed and placed under a balloon ofhydrogen. After 2 h at RT, the mixture was filtered over Celite® and thefiltrate was concentrated under reduced pressure to yield the titlecompound. MS: 227 (M+1).

The following intermediates in table F were prepared according to schemeF using the procedure outlined in the synthesis of intermediate F1 or F2using commercially available, known or prepared phenols in step 1 andemploying various azodicarboxylates with TBAD being the preferredreagent. In cases where additional chemical manipulation are to becarried out on the intermediate, the second step may be omitted.

TABLE F Intermediate Structure Name MS (M + 1) F3

1-methyl-5-(piperidin- 4-yloxy)-1H-indazole 232 F4

4-phenoxypiperidine 178 F5

6-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-2- methylbenzo[d]oxazole 251F6

6-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-2- methylisoindolin-1-one 265F7

5-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-1-methyl-1H- indazole 250 F8

5-(((3R,4S)-3- fluoropiperidin-4- yl)oxy)-2- methoxypyridine 227 F9

5-((cis-3- fluoropiperidin-4- yl)oxy)-2- methoxypyridine 227 F10

5-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-1H-indazole 236 F11

2-cyclopropyl-6- (piperidin-4- yloxy)isoindolin-1-one 273 F12

3-(((3R,4S)-3- fluoropiperidin-4- yl)oxy)benzonitrile 221 F13

3-(((3S,4S)-3- fluoropiperidin-4- yl)oxy)benzonitrile 221 F14

3-(((3R,4R)-3- fluoropiperidin-4- yl)oxy)benzonitrile 221 F15

6-(piperidin-4-yloxy)- 1,2,3,4- tetrahydroquinoline 233 F16

5-(((3R,4S)-3- fluoropiperidin-4- yl)oxy)-1-methyl-1H- indazole 250 F17

5-(((3S,4S)-3- fluoropiperidin-4- yl)oxy)-1-methyl-1H- indazole 250 F18

5-(((3R,4R)-3- fluoropiperidin-4- yl)oxy)-1-methyl-1H- indazole 250 F19

5-(piperidin-4-yloxy)- 1H-indole 217 F20

1-methyl-5-(piperidin- 4-yloxy)-1H-indole 231 F21

2-fluoro-5-(piperidin-4- yloxy)pyridine 197 F22

2-methoxy-5-((trans-3- methylpiperidin-4- yl)oxy)pyridine 223 F23

2-methoxy-5-((cis-3- methylpiperidin-4- yl)oxy)pyridine 223 F24

2-isopropoxy-5- (piperidin-4- yloxy)pyridine 237 F25

(3S,4R)-3-fluoro-4- phenoxypiperidine 196 F26

2-cyclobutoxy-5- (piperidin-4- yloxy)pyridine 249 F27

4-((2,3- dihydrobenzo[b][1,4] dioxin-6- yl)oxy)piperidine 236 F28

(3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3- fluoropiperidine 238F29

(3S,4R)-4-((1,3- dihydro-2-benzofuran- 4-yl)oxy)-3- fluoropiperidine 238F30

(3R,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3- fluoropiperidine 238F31

6-((6-methoxypyridin- 3-yl)oxy)-3- azabicyclo[3.1.1]heptane 221 F32

5-(piperidin-4- yloxy)nicotinonitrile 204 F33

3-methoxy-5- (piperidin-4- yloxy)pyridine 208 F34

3-(piperidin-4-yloxy)- 7,8-dihydro-5H- pyrano[4,3-b]pyridine 235 F35

tert-butyl 4-(3- cyanophenoxy)piperidine- 1-carboxylate 206* F36

3-(piperidin-4-yloxy)- 6,7-dihydro-5H- cyclopenta[b]pyridine 219 F37

6-(piperidin-4-yloxy)- 3,4-dihydro-2H- pyrano[2,3-b]pyridine 235 F38

(3S,4R)-3-fluoro-4-(4- fluorophenoxy)piperidine 214 F39

4-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-5,7- dihydrofuro[3,4-b]pyridine 239 F40

4-(((3R,4R)-3- fluoropiperidin-4- yl)oxy)-5,7- dihydrofuro[3,4-b]pyridine 239 F41

3-methyl-5-(piperidin- 4-yloxy)pyridine 193 F42

(3S,4R)-3-fluoro-4- (isochroman-6- yloxy)piperidine 252 F43

(3S,4R)-3-fluoro-4- (isochroman-7- yloxy)piperidine 252 *MS Data is for(M + 1 − Boc)

Intermediate G is prepared from a commercial alcohol G-1 (wherein PG isan amine protecting group), which after reaction with4-(trifluoromethyl)benzenesulfonyl chloride forms adduct G-2.Displacement of sulfone G-2 by a known or prepared phenol or alcohol(wherein Ar is an aromatic or heteroaromatic ring of R¹) is carried outunder the action of K₃PO₄ or Cs₂CO₃ to provide ether G-3. Deprotectionunder acidic or reductive conditions provides intermediate G.

Intermediate G1

4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidine (Scheme G) Step 1:Benzyl4-(((4-(trifluoromethyl)phenyl)sulfonyl)oxy)piperidine-1-carboxylate

A solution of benzyl 4-hydroxypiperidine-1-carboxylate (200 g, 808 mmol)and DCM (2 L) was cooled below 10° C. 4-(Trifluoromethyl)benzenesulfonylchloride (296 g, 1.21 mol) was added followed by triethylamine (169 mL,1.21 mol) and 4-dimethylaminopyridine (9.87 g, 81 mmol). The reactionwas aged at 5° C. and slowly warmed to RT. The reaction was aged 14 hand was transferred to separatory funnel containing an aqueous 10%citric acid solution. The organic was dried over anhydrous Na₂SO₄ beforeconcentrating to dryness. The residue was purified by silica gel column(0-50% EtOAc in hexanes) to give the title compound.

Step 2: Benzyl4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidine-1-carboxylate

To a flask was added benzyl4-(((4(trifluoromethyl)phenyl)sulfonyl)oxy)piperidine-1-carboxylate(73.3 g, 165 mmol) and 1,3-dihydro-2-benzofuran-5-ol (15 g, 110 mmol), afine powder of potassium tribasic phosphate (35.1 g, 165 mmol) and MeCN(150 mL). After being stirred at 60° C. for an appropriate period, themixture was cooled and poured into water and then extracted with EtOAc.The organic layer was dried over anhydrous Na₂SO₄ before concentratingto dryness. The residue was purified by silica gel column (0-50% EtOAcin hexanes) to give the title compound.

Step 3: 4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidine

To a solution of benzyl4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidine-1-carboxylate (9.7 g,27.4 mmol) in methanol (194 mL) was added Pd/C (10 wt %, 0.877 g, 2.74mmol) under an atmosphere of N₂(g). The system was purged and was placedunder a balloon of H₂(g) with stirring at RT. Upon completion, thereaction was filtered and the filtrate was concentrated to provide thetitle compound, which was carried forward without further purification.MS: 220 (M+1). The following intermediates in table G were preparedaccording to scheme G using the procedure outlined in the synthesis ofintermediate G1. Alternative conditions are: (1) using tert-butyl4-hydroxypiperidine-1-carboxylate in step 1, (2) using the combinationof cesium carbonate as a base and DMF as the solvent in step 2, and (3)using TFA or HCl for N-Boc deprotection. In some cases, step 3 may beomitted to furnish the N-protected piperidine intermediate.

TABLE G Intermediate Structure Name MS (M + 1) G2

3-(piperidin-4-yloxy)- 5,7-dihydrofuro[3,4- b]pyridine 221 G3

4-(4- (methoxymethyl)phenoxy) piperidine 222 G4

3-methyl-5-(piperidin- 4-yloxy)-1H- pyrazolo[3,4-b]pyridine NMR data¹ G5

4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidine 220 G6

4-((2-(benzyloxy)-2,3- dihydro-1H-inden-5- yl)oxy)piperidine 324 G7²

4-((1-methyl-1,3- dihydro-2-benzofuran- 5-yl)oxy)piperidine 234 G8

4-(isochroman-7- yloxy)piperidine 234 G9³

2-(methoxymethyl)-5- (piperidin-4- yloxy)pyridine 223 G10

2-((2- methoxyethoxy)methyl)- 5-(piperidin-4- yloxy)pyridine 267 G11⁴

4-(4-((2- methoxyethoxy)methyl) phenoxy)piperidine 266 G12

5-(piperidin-4-yloxy)- 1H-pyrazolo[3,4- b]pyridine 219 G13⁵

4-(isochroman-6- yloxy)piperidine 234 G14⁶

4-((2,2- difluorobenzo[d][1,3]dioxol- 5-yl)oxy)piperidine 258 G15

1,2-dimethyl-5- (piperidin-4-yloxy)- 1H-benzo[d]imidazole 246 G16

1,2-dimethyl-6- (piperidin-4-yloxy)- 1H-benzo[d]imidazole 246 G17

methyl 2-(5-(piperidin- 4-yloxy)-1H-indazol-1- yl)acetate 290 G18

4-(3- (methylsulfonyl)phenoxy) piperidine 256 G19

2-((piperidin-4- yloxy)methyl)pyridine 193 G20

4-((1-methyl-1H- pyrazol-4- yl)oxy)piperidine 182 G21

6-(piperidin-4-yloxy)- 2,3-dihydrofuro[3,2- b]pyridine 221 G22⁷

5-(piperidin-4-yloxy)- 1,3- dihydrobenzo[c]thiophene 2,2-dioxide 268 G23

6-(piperidin-4-yloxy)- [1,2,4]triazolo[1,5- a]pyridine 219 G24

6-(piperidin-4- yloxy)imidazo[1,2- a]pyridine 218 G25

5-(piperidin-4-yloxy)-1,3- dihydrobenzo[c]thiophene 2-oxide 252 G26

2-methyl-5-(piperidin- 4-yloxy)-2H-indazole 232 G27⁸

tert-butyl 4-((1-(2- methoxyethyl)-1H- pyrazol-3- yl)oxy)piperidine-1-carboxylate 326 G28

7-((tert- butyldimethylsilyl)oxy)-3- (piperidin-4-yloxy)-6,7-dihydro-5H- cyclopenta[b]pyridine 349 G29

4-(2,2,2- trifluoroethoxy)piperidine 184 G30

4-((piperidin-4- yloxy)methyl)pyridine 193 G31

3-((piperidin-4- yloxy)methyl)pyridine 193 G32

4-((1-ethyl-1H-pyrazol- 4-yl)oxy)piperidine 196 G33⁹

4-((1-phenyl-1H- pyrazol-4- yl)oxy)piperidine 244 ¹¹H NMR (400 MHz,methanol-d₄): δ 8.32 (1 H, s), 8.04 (1 H, s), 4.49-4.53 (1 H, m),3.00-3.10 (2 H, m), 2.85-2.92 (2 H, m), 2.35 (3 H, s), 1.85-2.00 (2 H,m), 1.65-1.75 (2 H, m). ²Phenol may be prepared according to literatureprocedures, see e.g.: Wu, H.-J.; et at. J. Org. Chem. 1998, 63,5064-5070. ³Phenol may be prepared according to literature procedures,see e.g.: Klapars, A..; et al. J. Org. Chem. 2008, 73, 4986-4993.⁴Phenol may be prepared according to literature procedures, see e.g.:Saa, J. M..; et al. J. Org. Chem. 1988, 53, 4263-4273. ⁵Phenol may beprepared according to literature procedures, see e.g.: Schieler, L.;Sprenger, R. D. J. Am. Chem. Soc. 1951, 73, 4045-4046. ⁶Phenol may beprepared according to literature procedures, see e.g.: Yoshihiro, et al.PCT Patent Publ'n WO2011/059021. ⁷Phenol may be prepared according toliterature procedures, see e.g.: Kanematsu, K.; Kinoyama, I. J. Chem.Soc., Chem. Commun. 1992, 10, 735-736. ⁸Phenol may be prepared accordingto literature procedures, see e.g.: Kanouni, et al. PCT Patent Publ'nWO2014/151106. ⁹Phenol may be prepared according to literatureprocedures, see e.g.: Lamberth, C. Org. Prep. Proc. Int. 2002, 34,98-102.

Intermediate H is prepared from an S_(N)Ar reaction of intermediate Bwith commercial or prepared piperidin-4-ols.

Intermediate H1

2-(4-Hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme H)

A solution of2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (4 g, 21.9mmol, intermediate B1) in neat piperidin-4-ol (10.0 g, 99 mmol) wasstirred at 140° C. for 2 h. The reaction mixtue was cooled and water (20mL) was added. The mixture was stirred at RT for 30 min and theprecipitate was filtered to yield the title compound. MS: 248 (M+1).

The following intermediates in table H were prepared according to schemeH using the procedure outlined in the synthesis of intermediate H1 usingcommercially available or prepared piperidines with alternativeconditions of using NMP as solvent and sodium bicarbonate as the base.

TABLE H MS Intermediate Structure Name (M + 1) H2*

2-(3-hydroxy-8- azabicyclo[3.2.1]octan- 8-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 274 H3**

2-(3-hydroxy-8- azabicyclo[3.2.1]octan- 8-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 274 H4

3-ethyl-2-(4- hydroxypiperidin-1-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 262 *Intermediate H2 was synthesized usingexo-8-azabicyclo[3.2.1]octan-3-ol **Intermediate H3 was synthesizedusing endo-8-azabicyclo[3.2.1]octan-3-ol

Intermediate I is prepared from commercially available nicotinic acidI-1 and is transformed to the corresponding ester I-2 via abase-mediated alkylation. Selective cyanation of dichloride I-2 providesintermediate I.

Intermediate I1

Methyl 6-chloro-2-cyano-4-methylnicotinate (Scheme I) Step 1: Methyl2,6-dichloro-4-methylnicotinate

To a solution of 2,6-dichloro-4-methylnicotinic acid (10 g, 48.5 mmol)in DMF (162 mL) was added potassium carbonate (10.06 g, 72.8 mmol) andMet (12 mL, 192 mmol) at 0° C. The reaction mixture was stirred at RTfor 3 h and was subsequently poured into water. This mixture wasextracted with EtOAc and the organic layer was washed with water andbrine, dried over anhydrous sodium sulfate and concentrated in vacuo.The crude material was used without further purification.

Step 2: Methyl 6-chloro-2-cyano-4-methylnicotinate

A solution of methyl 2,6-dichloro-4-methylnicotinate (3 g, 13.6 mmol)and copper(I) cyanide (1.83 g, 20.5 mmol) in NMP (13.6 mL) was degassedand placed under nitrogen. The system was heated to 180° C. for 2 hunder microwave irradiation. The mixture was diluted with 10% aqueousammonium hydroxide (22 mL) and was filtered over Celite® (EtOAc wash).The organic layer was washed with water, dried over anhydrous sodiumsulfate and concentrated to dryness. The residue was purified by columnchromatography on silica gel (0-20% EtOAc in hexanes) to yield the titlecompound. MS: 211 (M+1).

The following intermediates in table I were prepared according to schemeI using the procedure outlined in the synthesis of intermediate I1 usingcommercially available nicotinic acids.

TABLE I Intermediate Structure Name MS (M + 1) I2

methyl 6-chloro-2- cyanonicotinate 197

Intermediate J is prepared according to Scheme J from intermediate Bafter treatment with base followed by an alkyl halide. Depending on thereagents and conditions utilized the mono-, bis- and tris-adducts maybeobtained.

Intermediate J1

2-Chloro-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (SchemeJ)

To 2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (5 g,27.4 mmol, intermediate B1) in DMSO (137 mL) was added LHMDS (1 M inTHF, 27.4 mL, 27.4 mmol). The reaction was sonicated and stirred at RTfor 10 min. Iodomethane (1.71 mL, 27.4 mmol) was added dropwise at RT.Upon reaction completion the reaction was diluted with water (600 mL),aqueous 1 M HCl (10 mL) and DCM (200 mL). The mixture was stirred andfiltered before the organic layer was separated, dried over anhydroussodium sulfate and concentrated. The residue was taken up in hot etherand upon cooling, the resultant solids were collected by filtration (1:1ether:heptanes wash) to yield the title compound. MS: 197 (M+1).

Intermediate J2

2-Chloro-3,6,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme J)

A solution of2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (5 g, 27.4mmol, intermediate B1), in DMF (200 mL), was flushed with N₂(g) beforeNaH (1.205 g, 30.1 mmol, 60%) was added at room temperature. Thereaction mixture was stirred at RT for 1 h, before iodomethane (7.77 g,54.8 mmol) was added. After stirring at for 2 h, it was heated to 65° C.for 3 h and was worked up with EtOAc and water. The organic layer wascollected and the major product was isolated after purification on asilica gel column (40% EtOAc in hexanes) to yield the title compound.MS: 211 (M+1).

Intermediate J3

2-Chloro-3,6,7,7-tetramethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme J)

From the same reaction as described in the procedure for intermediate J2(vide supra) was obtained the title compound as the minor product. MS:225 (M+1).

Intermediate K is prepared according to Scheme K from N-protectedpiperidine alcohol K-1 in a two-step procedure involving base-mediatedalkylation to form adduct K-2 and subsequent deprotection to reveal thepiperidine amine.

Intermediate K

4-(Cyclopropylmethoxy)piperidine (Scheme K) Step 1: tert-Butyl4-(cyclopropylmethoxy)piperidine-1-carboxylate

To a solution of tert-butyl 4-hydroxypiperidine-1-carboxylate (400 mg,1.987 mmol) in DMF (4 mL) was added sodium hydride (95 mg, 2.39 mmol,60%) at 0° C. The reaction was stirred for 1 h before(bromomethyl)cyclopropane (322 mg, 2.39 mmol) and sodium iodide (14.90mg, 0.099 mmol) were added. The reaction was stirred for 20 h at RT andthen the mixture was treated with water (25 mL) and extracted with DCM(25 mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by flashsilica gel chromatography (0-25% THF in petroluem ether) to give thetitle compound.

Step 2: 4-(Cyclopropylmethoxy)piperidine

A solution of tert-butyl 4-(cyclopropylmethoxy)piperidine-1-carboxylate(290 mg, 1.136 mmol) in 4 M HCl in EtOAc (3 mL) was stirred at RT for 1h. Volatiles were removed from the reaction under reduced pressure. Theresidue was dissolved in MeOH (2 mL) and basified by saturated aqueousNaHCO₃ to pH 8. The mixture was concentrated and the residue was treatedwith EtOAc (5 mL), filtered and concentrated to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 3.50-3.53 (1H, m), 3.28 (2H, d,J=6.8 Hz), 3.17-3.21 (2H, m), 2.87-2.90 (2H, m), 1.99-2.04 (2H, m),1.67-1.71 (2H, m), 1.06-1.03 (1H, m), 0.52-0.57 (2H, m), 0.17-0.21 (2H,m).

The following intermediates in table K were prepared according to schemeK using the procedure outlined in the synthesis of intermediate K1 usingcommercially available or prepared alkyl halides, mesylates ortosylates. In cases where additional chemical manipulation are to becarried out on the intermediate, the second step may be omitted.

TABLE K Intermediate Structure Name MS (M + 1) K2

benzyl 4-((2- methylallyl)oxy)piperidine- 1-carboxylate 290 K3

4- (cyclobutylmethoxy) piperidine 170 K4

4-(2-(azetidin-1- yl)ethoxy)piperidine 278 K5

N-(2-(piperidin-4- yloxy)ethyl)acetamide 280 K6

4- (cyclopentylmethoxy) piperidine NMR data¹ K7

1-((piperidin-4- yloxy)methyl)cyclo- propane-1-carbonitrile NMR data² K8

tert-butyl 4-((3- methylbut-2-en-1- yl)oxy)piperidine-1- carboxylate 184* K9

2-((piperidin-4- yloxy)methyl)oxazole 183 K10

benzyl 4-(2- methylenebutoxy)piper- idine-1-carboxylate 304 K11

4- (bicyclo[1.1.1]pentan- 1-ylmethoxy)piperidine 182 K12

4-((2- methylallyl)oxy)piperidine NMR data³ K13

tert-butyl 4-((1-(((tert- butyldimethylsilyl)oxy) methyl)cyclopropyl)methoxy)piperidine-1- carboxylate 400 K14

4-((2,2-difluoro-1- methylcyclopropyl) methoxy)piperidine 206 K15

4-(((trans)-2- (trifluoromethyl)cyclo- propyl)methoxy)piperidine 222 K16

benzyl 4- (allyloxy)piperidine-1- carboxylate 276 K17

4-(2-(1- methylcyclopropyl) ethoxy)piperidine 184 K18

4-((1-methyl-1H- pyrazol-4- yl)methoxy)piperidine 196 K19

tert-butyl 4-((1- hydroxycyclopropyl) methoxy)piperidine-1- carboxylate306 K20

tert-butyl 4-((2- methylallyl)oxy)piperidine- 1-carboxylate  156* K21

benzyl-(3S,4S)-3- fluoro-4-((2- methylallyl)oxy)piperidine-1-carboxylate 308 K22

benzyl (3S,4R)-3- fluoro-4-((2- methylallyl)oxy)piperidine-1-carboxylate 308 *MS data is equal to (M + 1 − Boc) ¹¹H NMR (400 MHz,methanol-d₄): δ 3.59-3.68 (m, 1 H), 3.35 (d, J = 6.80 Hz, 2 H),3.20-3.25 (m, 2 H), 3.03-3.14 (m, 2 H), 2.09-2.16 (m, 1 H), 1.91-2.03(m, 2 H), 1.81-1.88 (m, 2 H), 1.67-1.75 (m, 2 H), 1.45-1.65 (m, 4 H),1.16-1.36 (m, 2 H). ²¹H NMR (400 MHz, CDCl₃): δ 3.71-3.73 (1 H, m), 3.48(2 H, s), 3.17-3.21 (2 H, m), 3.84-3.87 (2 H, m), 1.98-2.02 (2 H, m),1.69-1.73 (2 H, m), 1.26-1.30 (2 H, m), 0.98-1.00 (2 H, m). ³¹H NMR (500MHz, CDCl₃): δ 7.78 (s, 1 H), 6.11 (br s, 1 H), 5.01 (s, 1 H), 4.90 (s,1 H), 4.34 (s, 2 H), 3.97 (s, 2 H), 3.55 (m, 3 H), 3.03 (t, 2 H), 2.34(s, 3 H), 2.02 (s, 2 H), 1.78 (m, 5 H).

Intermediate L (wherein R is independently selected from fluoro andC₁₋₆alkyl) is prepared according to Scheme L from N-protected piperidinealcohol intermediate K in a two-step procedure involving Simmons-Smithreaction to form adduct L-1 and subsequent deprotection to reveal thepiperidine amine.

Intermediate L1

4-((1-Methylcyclopropyl)methoxy)piperidine (Scheme L) Step 1: Benzyl4-((1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of benzyl 4-((2-methylallyl)oxy)piperidine-1-carboxylate(9 g, 31.1 mmol) in DCM (100 mL) were added diiodomethane (41.7 g, 156mmol) and diethylzinc (93 ml, 93 mmol) at −5° C. for 3 h. The reactionmixture was diluted with water (100 mL) and extracted with EtOAc (100mL×3). The combined organic layers were washed with brine (80 mL), driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by chromatography column(15% EtOAc in petroleum ether) to give the title compound.

Step 2: 4-((1-Methylcyclopropyl)methoxy)piperidine

To a solution of benzyl4-((1-methylcyclopropyl)methoxy)piperidine-1-carboxylate (1 g, 3.30mmol) in MeOH (10 mL) was added Pd/C (10 wt %, 3.51 g, 3.30 mmol). Thereaction was stirred under an atmosphere of H₂ (15 psi) at RT for 1 h.The mixture was filtered and the filtrate was concentrated in vacuo toyield the title compound. MS: 170 (M+1).

Intermediate L1A

(3S,4R)-3-Fluoro-4-((1-methylcyclopropyl)methoxy)piperidine (Scheme L)Step 1: (3S,4R)-Benzyl4-((1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

(3S,4R)-Benzyl 3-fluoro-4-((2-methylallyl)oxy)piperidine-1-carboxylate(2.08 g, 6.77 mmol) was dissolved in DCM (40 mL) and the solution wascooled to 0° C. under a nitrogen atmosphere. Diiodomethane (2.73 mL,33.8 mmol) was added followed by the dropwise addition of diethylzinc (1M in hexanes, 20.3 mL, 20.3 mmol). The reaction was allowed to stir for16 h and was allowed to gradually warm to RT. The reaction was carefullyquenched with aqueous NaHCO₃ (saturated) and once gas evolution ceasedthe mixture was diluted with DCM. The milky suspension was filtered andthen the filtrate was partitioned with water followed by brine. Theorganic was dried over anhydrous sodium sulfate, filtered andconcentrarted before purification by silica gel chromatography (10-40%EtOAc/hexanes) to afford the title compound. MS: 322 (M+1).

Step 2: (3S,4R)-3-Fluoro-4-((1-methylcyclopropyl)methoxy)piperidine

(3S,4R)-Benzyl3-fluoro-4-((1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(1.86 g, 5.79 mmol) was dissolved in MeOH (25 mL). The system wasevacuated and placed under a nitrogen atmosphere, then palladiumhydroxide on carbon (20%, 0.406 g, 0.579 mmol) was added. The system wasplaced under a hydrogen atmosphere and was stirred for 3 h before themixture was filtered (MeOH wash) and concentrated to afford the titlecompound that was used without further purification. MS: 188 (M+1).

The following intermediates in table L were prepared according to schemeL using the procedure outlined in the synthesis of intermediate L1. Incases where the piperidine is Boc-protected, use an acid such was HCl orTFA for step 2. Additionally step 2 may be omitted when subsequentchemical manipulations are required.

TABLE L Intermediate Structure Name MS (M + 1) L2

tert-butyl 4-((2,2- dimethylcyclopropyl) methoxy)piperidine-1-carboxylate  184* L3

4-((1- ethylcyclopropyl)meth- oxy)piperidine 184 L4

(3S,4R)-4-((2,2- dimethylcyclopropyl) methoxy)-3- fluoropiperidine 188L5

(3R,4R)-4-((2,2- dimethylcyclopropyl) methoxy)-3- fluoropiperidine 188*MS Data is for (M + 1 − Boc)

Intermediate M is prepared according to scheme M from ether M-1, whichis prepared using 6-fluoropyridin-3-ol in step 1 of the procedureoutlined in the synthesis of intermediate F. S_(N)Ar with an alcohol oramine in the presence of base provides adduct M-2. Deprotection ofpiperidine amine M-2 provides intermediate M.

Intermediate M1

2-(2-Methoxyethoxy)-5-(piperidin-4-yloxy)pyridine (Scheme M) Step 1:tert-Butyl4-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of 2-(dimethylamino)ethanol (75 mg, 0.844 mmol) in DMF (2mL) was added sodium hydride (33.7 mg, 0.844 mmol, 60%) at 0° C. Themixture was stirred for 20 min under an atmosphere of nitrogen.Tert-Butyl 4-((6-fluoropyridin-3-yl)oxy)piperidine-1-carboxylate (50 mg,0.169 mmol) was added to the mixture and the reaction was graduallywarmed to 50° C. and stirred for 18 h. The reaction was quenched with50% aqueous NH₄Cl (40 mL) and the mixture was extracted with EtOAc (20mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by prep-TLC(10:1 DCM:MeOH) to yield the title compound.

Step 2: 2-(2-Methoxyethoxy)-5-(piperidin-4-yloxy)pyridine

A solution of tert-butyl4-((6-(2-(dimethylamino)ethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate(50 mg, 0.142 mmol) in HCl (4 M in MeOH, 2 mL) was stirred at 20° C. for1 h. The reaction was concentrated to give the title compound as thebis-HCl salt. MS: 253 (M−2HCl+H).

The following intermediates in table M were prepared according to schemeM using the procedure outlined in the synthesis of intermediate M1 usingcommercially available alcohols in step 1. In cases where additionalchemical manipulations are required, step 2 may be omitted.

TABLE M Intermediate Structure Name MS (M + 1) M2

2-methyl-1-((5- (piperidin-4- yloxy)pyridin-2- yl)oxy)propan-2-amine 266M3

2-((5-(piperidin-4- yloxy)pyridin-2- yl)oxy)ethan-1-ol 239 M4

N,N-dimethyl-2-((5- (piperidin-4- yloxy)pyridin-2- yl)oxy)ethan-1-amine266 M5

2-ethoxy-5-(piperidin- 4-yloxy)pyridine 223 M6

tert-butyl 4-((6-(2- hydroxyethoxy)pyridin- 3-yl)oxy)piperidine-1-carboxylate 339 M7

5-(((3R,4R)-3- fluoropiperidin-4- yl)oxy)-2-(2- methoxyethoxy)pyridine271 M8

5-(((3S,4R)-3- fluoropiperidin-4- yl)oxy)-2-(2- methoxyethoxy)pyridine271

Intermediate N is prepared according to scheme N from piperidone N-1,which is reduced to the alcohol N-2. Reductive conditions in thepresence of Boc-anhydride provides intermediate N1 as a trans-racemicmixture. Inversion of the alcohol is accomplished in a two-stepprocedure of a Mitsunobu reaction with benzoic acid to provide adductN-3 and saponification to give intermediate N2 as a cis-racemic mixture.

Intermediate N1

tert-Butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate (Scheme N)Step 1: trans-1-Benzyl-3-methylpiperidin-4-ol

Into a 5 L 4-necked round-bottom flask was placed water (1.04 L),methanol (450 mL), and 1-benzyl-3-methylpiperidin-4-one (150 g, 739mmol). This was followed by the addition of H₃PO₄ (85.1 g, 738 mmol,85%) dropwise with stirring at −10° C. NaBH₄ (56.0 g, 1.47 mol) wasadded in portions at −10° C. over 5 h. The resulting solution wasstirred for 16 h at RT. The pH of the solution was adjusted to ˜9 with 5M aqueous sodium hydroxide. The resulting solution was extracted withethyl acetate (200 mL×3). The organic layers were combined and treatedwith 2 M HCl to pH˜5. The aqueous layer was adjusted to pH˜9 with 5 Maqueous sodium hydroxide. The resulting solution was extracted withethyl acetate (200 mL×3). The organic layers were combined, washed withbrine (300 mL×2), dried over anhydrous sodium sulfate and concentratedin vacuo.

Step 2: tert-Butyl trans-4-hydroxy-3-methylpiperidine-1-carboxylate

Into a 2 L 4-necked round-bottom flask was added methanol (850 mL), Pd/Ccarbon (10%, 25 g), trans-1-benzyl-3-methylpiperidin-4-ol (56 g, 273mmol) and di-tert-butyl dicarbonate (65.5 g, 300 mmol) under anatmosphere of nitrogen. The resulting mixture was stirred for 20 h underan atmosphere of H₂ at RT. The solids were removed by filtration and thefiltrate was concentrated under vacuum. The residue was dissolved in DCM(500 mL) and was washed with water (300 mL) and brine (300 mL). Theorganic phase was dried over anhydrous Na₂SO₄ and concentrated undervacuum to yield the title compound. ¹H NMR (400 MHz, CDCl₃): δ 0.93-1.01(3H, m), 1.30-1.53 (11H, m), 1.89-1.92 (1H, d, J=12.8 Hz), 2.43-2.49(1H, m), 2.80-2.86 (1H, m), 3.27-3.32 (1H, m), 3.94-4.05 (2H, m).

Intermediate N2

tert-Butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate (Scheme N)Step 1: tert-Butyl cis-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate

To a 5 L 4-necked round-bottom flask was placed tetrahydrofuran (853mL), benzoic acid (101.5 g, 832 mmol), triphenylmethane (217.8 g, 831mmol) and trans-tert-butyl 4-hydroxy-3-methylpiperidine-1-carboxylate(135.3 g, 629 mmol, intermediate N1). Diethyl azodicarboxylate (144.8 g,832.2 mmol) in tetrahydrofuran (500 mL) was added dropwise to thereaction at 0° C. The resulting solution was stirred 15 h at RT. Theresulting mixture was concentrated under vacuum and the residue wasapplied directly onto a silica gel column (0:1-1:20 ethylacetate:petroleum ether) to yield the title compound.

Step 2: tert-Butyl cis-4-hydroxy-3-methylpiperidine-1-carboxylate

To a 5-L 3-necked round-bottom flask was placed methanol (3.5 L), sodiumhydroxide (109 g, 2.72 mol), and tert-butylcis-4-(benzoyloxy)-3-methylpiperidine-1-carboxylate (173.5 g, 544 mmol)in methanol. The resulting solution was stirred for 2 h at RT beforeremoving volatiles under reduced pressure. The residue was partitionedwith EtOAc (1 L) and water (500 mL). The organic layer was washed withwater (500 mL) and brine (500 mL), dried over anhydrous sodium sulfateand concentrated in vacuo. The residue was applied onto a silica gelcolumn and eluted with (1:10-1:5 ethyl acetate:petroleum ether) toprovide the title compound. ¹H NMR (400 MHz, CDCl₃): δ 0.93-1.00 (3H,m), 1.46 (9H, m), 1.62-1.69 (2H, m), 1.74-1.80 (1H, m), 3.03-3.09 (1H,m), 3.30-3.36 (1H, m), 3.50-3.58 (2H, m), 3.87-3.88 (1H, m).

Intermediate O is prepared according to scheme O from ether O-1, whichis prepared using 6-bromopyridin-3-ol in step 1 of the procedureoutlined in the synthesis of intermediate F. Palladium-mediated C—Narylation with a commericially available amine provides adduct O-2.Deprotection of piperidine amine O-2 provides intermediate O.

Intermediate O

N-(2-(benzyloxy)ethyl)-5-(piperidin-4-yloxy)pyridin-2-amine (Scheme O)Step 1: tert-Butyl 4-((6-bromopyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of 6-bromopyridin-3-ol (2 g, 11.5 mmol), tert-butyl4-hydroxypiperidine-1-carboxylate (2.78 g, 13.79 mmol) and(E)-di-tert-butyl diazene-1,2-dicarboxylate (3.97 g, 17.24 mmol) intoluene (80 mL) was added triphenylphosphine (4.52 g, 17.24 mmol). Thereaction mixture was stirred at 80° C. for 15 h before volatiles wereremoved under reduced pressure. The crude material was purified bysilica gel chromatography (0-10% EtOAc in petroleum ether) to yield thetitle compound.

Step 2: tert-Butyl4-((6-((2-(benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((6-bromopyridin-3-yl)oxy)piperidine-1-carboxylate (200 mg, 0.280mmol), 2-(benzyloxy)ethanamine (50.8 mg, 0.336 mmol), sodium2-methylpropan-2-olate (81 mg, 0.840 mmol), and2-(dicyclohexylphosphino)-2′,4′,6′-triisopropylbiphenyl (13.34 mg, 0.028mmol) in THF (5 mL) was added tris(dibenzylideneacetone)dipalladium(0)(25.6 mg, 0.028 mmol). The reaction mixture was stirred at 70° C. for 15h before cooling to RT and partitioning with water (10 mL) and EtOAc (10mL×3). The combined organic layers were washed with water (20 mL×3),dried with anhydrous sodium sulfate, filtered and concentrated underreduced pressure. The residue was purified by prep-TLC (1/1EtOAc/petroleum ether) to provide the title compound.

Step 3: N-(2-(benzyloxy)ethyl)-5-(piperidin-4-yloxy)pyridin-2-amine

To a solution of tert-butyl4-((6-((2-(benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidine-1-carboxylate(100 mg, 0.234 mmol) in DCM (5 mL) was added TFA (0.5 mL). The reactionmixture was stirred at 10° C. for 1 h and the solvent was evaporatedunder reduced pressure to give the title compound that was used withoutfurther purification. MS: 328 (M+1).

Intermediate P is prepared from 4-pyridinol P-1 which is transformed toether P-2 via an Mitsunobu reaction with a commerically availablealcohol. Hydrogenation of piperidine P-2 with a platinum catalystprovides intermediate P.

Intermediate P1

4-((1-Methylcyclopentyl)methoxy)piperidine (Scheme P) Step 1:4-((1-Methylcyclopentyl)methoxy)pyridine

To a solution of (1-methylcyclopentyl)methanol (100 mg, 0.87 mmol),pyridin-4-ol (100 mg, 1.05 mmol) and triphenylphosphine (345 mg, 1.31mmol) in toluene (5 mL) was added TBAD (302 mg, 1.31 mmol). The reactionmixture was stirred at 80° C. for 15 h. The reaction mixture cooled andthen directly purified by prep-TLC (1/1 EtOAc/petroleum ether) to yieldthe title compound.

Step 2: 4-((1-Methylcyclopentyl)methoxy)piperidine

To a solution of 4-((1-methylcyclopentyl)methoxy)pyridine (30 mg, 0.157mmol) in AcOH (5 mL) was added platinum(IV) oxide (3.56 mg, 0.016 mmol).The reaction mixture was stirred at 15° C. for 15 h under an atmosphereof H₂ (50 psi). The reaction mixture was filtered and the filtrate wasevaporated under reduced pressure to give the title compound, which wasused without further purification. MS: 198 (M+1).

The following intermediates in table P were prepared according to schemeP using the procedure outlined in the synthesis of intermediate P1 usingcommercially available alcohols in step 1.

TABLE P Intermediate Structure Name MS (M + 1) P2

methyl 2-cyano-5- methyl-6-(4- ((tetrahydrofuran- 3-yl)methoxy)piperidin- 1-yl)nicotinate 186 P3

4-((1- fluorocyclopentyl)meth- oxy)piperidine 202 P4

4- (neopentyloxy)piperidine 172 P5

4-((1- methylcyclobutyl)meth- oxy)piperidine 184 P6

4-(3,3,3-trifluoro-2- methylpropoxy)piperidine 212 P7

4-((1- (trifluoromethyl)cyclo- propyl)methoxy)piperidine NMR data* *¹HNMR (400 MHz, methanol-d₄): δ 3.57-3.69 (1 H, m), 3.31 (2 H, s),2.87-2.98 (2 H, m), 2.22-2.35 (2 H, m), 1.81-1.90 (2 H, m), 1.53-1.64 (2H, m), 1.31-1.36 (2 H, m), 0.77-0.90 (2 H, m).

Intermediate Q is prepared from a product from intermediate M6 which isoxidized to the corresponing aldehyde Q-1 after reaction withDess-Martin periodinane. Nucleophilic trifluoromethylation is carriedout with the Ruppert-Prakash reagent in conjunction with TBAF to providethe adduct Q-2. Subsequent deprotection of piperidine Q-2 with an acidprovides intermediate Q.

Intermediate Q

1,1,1-Trifluoro-3-(piperidin-4-yloxy)propan-2-ol (Scheme Q) Step 1:tert-Butyl 4-((6-(2-oxoethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate

To a solution of the tert-butyl4-((6-(2-hydroxyethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate (400mg, 1.18 mmol, intermediate M6) in DCM (2.3 mL) 0° C. was addedDess-Martin periodinane (752 mg, 1.77 mmol). The resulting mixture wasstirred at RT for 1 h. The mixture was partitioned with DCM and 1:1mixture of saturated NaHCO₃(aq) and 1.5 M Na₂S₂O₃(aq). The organic layerwas washed with water, then brine and dried over anhydrous MgSO₄,filtered, and concentrated under reduced pressure to yield the titlecompound.

Step 2: tert-Butyl4-((6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate

A solution of tert-butyl4-((6-(2-oxoethoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate (300 mg,0.892 mmol) and CsF (135 mg, 0.892 mmol) in THF (10 mL) was stirred atRT for 1 h. Trimethyl(trifluoromethyl)silane (127 mg, 0.892 mmol) wasadded and the reaction was stirred for 16 h. The mixture was treatedwith TBAF (1.78 mL, 1.78 mmol) and was stirred for 30 min and thevolatiles were removed to yield the title compound as a crude materialthat was carried forward without further purification.

Step 3: 1,1,1-Trifluoro-3-(piperidin-4-yloxy)propan-2-ol

To a solution of tert-butyl4-((6-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-3-yl)oxy)piperidine-1-carboxylate(200 mg, 0.492 mmol) in DCM (10 mL) was added TFA (2 mL, 26.0 mmol). Themixture was stirred at 20° C. for 1 h. The reaction was concentrated andwas purified by HPLC (ACN/water with 0.1% TFA modifier) to give thetitle compound. MS: 198 (M+1).

Intermediate R is prepared via S_(N)Ar reaction of commerciallyavailable piperidine R-1 and 1-fluoro-4-nitrobenzene. A two stepprocedure for the reduction of the aryl nitro R-2 is achieved by apalladium-catalyzed hydrogenation to form aniline R-3 and subsequentdiazotization to produce phenyl ether R-4. Acid-mediated deprotection ofN-Boc piperidine R-4 provides intermediate R.

Intermediate R

3,3-Difluoro-4-phenoxypiperidine (Scheme R) Step 1: tert-Butyl3,3-difluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate

To a solution of tert-butyl3,3-difluoro-4-hydroxypiperidine-1-carboxylate (800 mg, 3.37 mmol) inTHF (8 mL) was added potassium 2-methylpropan-2-olate (757 mg, 6.74mmol). A solution of 1-fluoro-4-nitrobenzene (523 mg, 3.71 mmol) in DMF(1 mL) was added to the mixture, the reaction was stirred at 50° C. for5 h under an atmosphere of N₂(g). Upon completion the reaction wasconcentrated and the residue was purified by silica gel chromatography(10/1 petroleum ether/EtOAc) to give the title compound.

Step 2: tert-Butyl4-(4-aminophenoxy)-3,3-difluoropiperidine-1-carboxylate

To a solution of tert-butyl3,3-difluoro-4-(4-nitrophenoxy)piperidine-1-carboxylate (840 mg, 2.344mmol) in EtOAc (15 mL) was added Pd/C (10%, 100 mg, 0.094 mmol). Thereaction was stirred at RT under an atmosphere of H₂(g) for 4 h. Themixture was filtered and washed with MeOH (20 mL×4) and the filtrate wasconcentrated to yield the title compound, which was carried forwardwithout further purification.

Step 3: tert-Butyl 3,3-difluoro-4-phenoxypiperidine-1-carboxylate

To a solution of tert-butyl4-(4-aminophenoxy)-3,3-difluoropiperidine-1-carboxylate (700 mg, 2.132mmol) in DMF (10 mL) was added tert-butyl nitrite (440 mg, 4.26 mmol).The resulting mixture was stirred at 50° C. under a N₂ atmosphere for 1h. The reaction mixture was quenched with water (30 mL) and extractedwith EtOAc (20 mL×3). The combined organic layers were washed with brine(40 mL), dried over anhydrous sodium sulfate, filtered, and concentratedin vacuo. The residue was purified by silica gel chromatography(50:1-2:1 petroleum ether:EtOAc) to give the title compound.

Step 4: tert-Butyl 3,3-difluoro-4-phenoxypiperidine-1-carboxylate

To a solution of tert-butyl3,3-difluoro-4-phenoxypiperidine-1-carboxylate (330 mg, 1.05 mmol) inEtOAc (5 mL) was added HCl (4 N in dioxane, 2.0 mL, 24.4 mmol). Thereaction was stirred at 27° C. for 1 h before quenching with aqueousNaOH (10 mL, 2 M) and partitioning with EtOAc (10 mL×3). The combinedorganic layers were washed with brine (10 mL), dried over sodiumsulfate, filtered, and concentrated in vacuo to give the title compound.MS: 214 (M+1).

Intermediate S is prepared according to scheme S beginning withintermediate F, which has a nitrile substituent. First, a reduction withDIBAL furnishes aldehyde S-2 and then the corresponding alcohol S-3 isobtained after reaction with sodium borohydride. Alkylation of thealcohol S-3 with a commericially available alkyl iodide provides etherS-4. Acid-mediated deprotection of N-Boc piperidine S-4 providesintermediate S.

Intermediate S1

4-(3-(Methoxymethyl)phenoxy)piperidine (Scheme S) Step 1: tert-Butyl4-(3-formylphenoxy)piperidine-1-carboxylate

Diisobutylaluminum hydride (6.61 mL, 6.61 mmol) was added to a stirred,cooled −78° C. mixture of tert-butyl4-(3-cyanophenoxy)piperidine-1-carboxylate (1 g, 3.31 mmol, intermediateF35) in DCM (20 mL). The mixture was stirred at −78° C. for 1 h and wasthen quenched with aqueous, saturated Rochelle's salt and partitionedwith DCM. The organic layer was washed with brine, dried over anhydroussodium sulfate and concentrated to give the title compound.

Step 2: tert-Butyl 4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate

NaBH₄ (40.9 mg, 1.08 mmol) was added to a stirred, cooled 0° C. mixtureof tert-butyl 4-(3-formylphenoxy)piperidine-1-carboxylate (220 mg, 0.720mmol) in methanol (5 mL). The mixture was stirred at 0° C. for 1 h andwas concentrated under reduced pressure upon completion. The residue waspurified by silica gel column chromatography on silica gel (1/1EtOAc/hexane) to give the title compound.

Step 3: tert-Butyl 4-(3-(methoxymethyl)phenoxy)piperidine-1-carboxylate

NaH (32.3 mg, 0.807 mmol, 60%) was added to a stirred, cooled 0° C.mixture of tert-butyl4-(3-(hydroxymethyl)phenoxy)piperidine-1-carboxylate (124 mg, 0.403mmol) in DMF (5 mL). The mixture was stirred at 0° C. for 15 min beforeMeI (0.05 mL, 0.807 mmol) was added. The reaction was allowed togradually warm to RT and was stirred for 2 h. Water and EtOAc were addedto the reaction and the organic layer was separated, washed with brine,dried over anhydrous soldium sulfate and concentrated to give the titlecompound, which was used without further purification.

Step 4: 4-(3-(methoxymethyl)phenoxy)piperidine

HCl (4 N in dioxane, 5 mL, 20.0 mmol) was added to a stirred mixture oftert-butyl 4-(3-(methoxymethyl)phenoxy)piperidine-1-carboxylate (130 mg,0.403 mmol) in dioxane (5 mL). The mixture was stirred at RT for 12 hand upon reaction completion the volatiles were removed under reducedpressure. The residue was purified by silica gel column chromatography(15/1 DCM/2 N NH₃ in MeOH) to yield the title compound. MS: 222 (M+1).

The following intermediates in table S were prepared according to schemeS using the procedure outlined in the synthesis of intermediate S1 usingcommercially available alkyliodides in step 3.

TABLE S Intermediate Structure Name MS (M + 1) S2

4-(3-((2- methoxyethoxy)methyl) phenoxy)piperidine 266

Intermediate T is prepared according to scheme T beginning with olefinT-1, which is reacted with mCPBA to form epoxide T-2. A base-mediatedring-opening reaction with commercial phenol provides adduct T-3, whichprovides intermediate T after an acid-mediated deprotection.

Intermediate T

3-((trans-3-Hydroxypiperidin-4-yl)oxy)benzonitrile (Scheme T) Step 1:cis-tert-Butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate

To a 1 L flask, with a large stir bar, is added tert-butyl5,6-dihydropyridine-1(2H)-carboxylate (24.15 g, 132 mmol) and DCM (440mL). The vessel is cooled in an ice/water bath and 3-chloroperoxybenzoicacid (45.5 g, 264 mmol) is added in one portion. After stirring for 30min at 0° C., the cooling bath was removed and the mixture was allowedto stir for 24 h. To the suspension was added aqueous sodiummetabisulfite (10%, 200 mL), water (100 mL) and DCM (200 mL) and wasthen stirred vigorously for 10 min. The organic layer is separated,washed with aqueous 1 N NaOH (3×200 mL), brine (200 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to yield the titlecompound.

Step 2: trans-tert-Butyl4-(3-cyanophenoxy)-3-hydroxypiperidine-1-carboxylate

To a 1 L flask with stir bar was added aqueous sodium hydroxide (1 M,9.54 g, 238 mmol), 3-hydroxybenzonitrile (28.4 g, 238 mmol) and water(139 mL). To that solution was added acetonitrile (380 mL) and then asolution of cis-tert-butyl7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate (25 g, 125 mmol) inacetonitrile (37 mL). Heat the reaction to reflux for 15 h. The reactionis cooled to RT and is poured in a separatory funnel containing water(400 mL) and DCM (800 mL). Separate the organic layer and wash with 2 NNaOH(aq) (200 mL), brine (200 mL) and dry over anhydrous Na₂SO₄, filterand concentrate in vacuo. The crude material was subjected to silica gelchromatography (0-50% EtOAc/hexanes) to yield the title compound.

Step 3: 3-((trans-3-Hydroxypiperidin-4-yl)oxy)benzonitrile hydrochloride

To a 500 mL flask with stir bar was added trans-tert-butyl4-(3-cyanophenoxy)-3-hydroxypiperidine-1-carboxylate (13.07 g, 41.1mmol) in dioxane (20 mL). To this solution is then added HCl (200 mL, 4N in dioxane). The reaction is stirred at RT for 2 h at which pointvolatiles removed under reduced pressure to yield the title compound.MS: 219 (M+1).

Intermediate U is prepared according to scheme U beginning withcommercially available aryl halide U-1. A Miyaura borylation reactionprovides boronic ester U-2 which is subsequently transformed by anoxidative hydroxylation to provide intermediate U.

Intermediate U1

Methyl 2-(5-hydroxy-1H-indazol-1-yl)acetate (Scheme U) Step 1: Methyl2-(1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)acetate

To a solution of methyl 2-(5-bromo-1-methyl-1H-indazol-3-yl)acetate (200mg, 0.706 mmol) in dioxane (5 mL) was added[1,1′-bis(diphenylphosphino)ferrocene]dichloro palladium(II) (51.7 mg,0.071 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane)(359 mg, 1.413 mmol) and potassium acetate (139 mg, 1.413 mmol). Thereaction mixture was degassed and purged with nitrogen. The reaction wasstirred 2 h at 80° C. and the mixture was filtered and concentrated togive the title compound.

Step 2: Methyl 2-(5-hydroxy-1H-indazol-1-yl)acetate

To a solution of methyl methyl2-(1-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazol-3-yl)acetate(200 mg, 0.606 mmol) in MeOH (4 mL) was added H₂O₂ (35%, 0.265 mL, 3.03mmol). The mixture was stirred at 25° C. for 16 h. The reaction wasquenched with aqueous, saturated Na₂SO₃ (10 mL) and then partitionedwith water (10 mL) and EtOAc (20 mL×3). The combined organic phases werewashed brine (5 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated. The residue was purified by reverse phase HPLC (ACN/waterwith 0.1% TFA modifier) to afford the title compound. MS: 221 (M+1).

The following intermediates in table U were prepared according to schemeU using the procedure outlined in the synthesis of intermediate U1 usingknown or prepared halides. In cases where the boronic ester or acid iscommercially available, the first step is omitted.

TABLE U Intermediate Structure Name MS (M + 1) U2

6-(2-((tert- butyldiphenylsilyl)oxy) propoxy)pyridin-3-ol 408 U3

6-(2,2,2- trifluoroethoxy)pyridin- 3-ol 194 U4

6- (trifluoromethoxy)pyri- din-3-ol 166 U5

4,4-dimethylchroman- 6-ol 178 U6

1,3-dimethyl-1H- indazol-5-ol 168 U7

tert-butyl 7-hydroxy- 2,3-dihydro-1H- pyrido[2,3- b][1,4]oxazine-1-carboxylate 253 U8

6-hydroxy-2- methylisoindolin-1-one 164 U9

2-cyclopropyl-6- hydroxyisoindolin-1- one 190 U10

6-isopropoxypyridin-3- ol 154 U11

6-cyclobutoxypyridin- 3-ol 166 U12

isochroman-7-ol NMR data¹ U13

6-((1-((tert- butyldiphenylsilyl)oxy) propan-2- yl)oxy)pyridin-3-ol 408U14

3-methyl-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-indazol-5- ol 280 U15

2-methyl-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-benzo[d]imidazol-5-ol 279 U16²

6-hydroxy-3- methyloxazolo[4,5- b]pyridin-2(3H)-one 167 U17

2-(benzyloxy)-2,3- dihydro-1H-inden-5-ol NMR data³ U18

6-((2- methoxyethoxy)methyl) pyridin-3-ol 184 U19⁴

1-((2- (trimethylsilyl)ethoxy) methyl)-1H- pyrazolo[3,4-b]pyridin- 5-ol266 U20⁵

tert-butyl 7-hydroxy- 2,3-dihydro-4H- benzo[b][1,4]oxazine-4-carboxylate  196⁶ U21

1,2-dimethyl-1H- benzo[d]imidazol-5-ol 163 U22

1,2-dimethyl-1H- benzo[d]imidazol-6-ol 163 U23⁷

methyl 2-(5-hydroxy- 1H-indazol-1-yl)acetate 207 U24

2,3-dihydrofuro[3,2- b]pyridin-6-ol 138 U25

[1,2,4]triazolo[1,5- a]pyridin-6-ol 136 U26

5-hydroxy-1,3- dihydrobenzo[c]thio- phene 2-oxide 169 U27⁸

2-methyl-2H-indazol- 5-ol 149 U28

7-((tert- butyldimethylsilyl)oxy)- 6,7-dihydro-5H-cyclopenta[b]pyridin-3- ol 266 ¹¹H NMR (400 MHz, CDCl₃): δ 6.92 (1 H, d,J = 8.0 Hz), 6.59 (1 H, dd, J = 8.0, 2.0 Hz), 6.39 (1 H, s), 5.05(1 H,br s), 4.65 (2 H, s), 3.89 (2 H, t, J = 6.0 Hz), 2.71 (2 H, t, J = 6.0Hz). ²Starting bromide may be prepared according to literatureprocedures, see e.g.: Hoveyda, et al., PCT Patent Publ'n WO2011/151434.³¹H NMR (400 MHz, CDCl₃): δ 7.27-7.42 (5 H, m), 7.03 (1 H, d, J = 8.0Hz), 6.64 (1 H, s), 6.60 (1 H, d, J = 8.0 Hz), 4.60 (2 H, s), 4.40-4.48(1 H, m), 3.06-3.17 (2 H, m), 2.92-3.03 (2 H, m). ⁴Starting bromide maybe prepared according to literature procedures, see e.g.: Ahrendt, etal., PCT Patent Publ'n WO2009/111279. ⁵Starting bromide may be preparedaccording to literature procedures, see e.g.: Mori, et al. PCT PatentPubl'n WO2013/151033. ⁶MS Data is for (M + 1 − tBu) ⁷Starting bromidemay be prepared according to literature procedures, see e.g.:Abeywardane, et al., PCT Patent Publ'n WO 2014/014874. ⁸Starting bromidemay be prepared according to literature procedures, see e.g.: Wang, etal., PCT Patent Publ'n WO2015/065937.

Intermediate V is prepared according to scheme V beginning with knownbromide V-1 (Partridge, B. M.; Hartwig, J. F. Org. Lett. 2013, 15,140-143). A palladium-catalyzed coupling reaction with an amine providesintermediate V.

Intermediate V

5-(Benzyloxy)-N-methylpyridin-2-amine (Scheme V)

To a solution of 5-(benzyloxy)-2-bromopyridine (200 mg, 0.757 mmol),methanamine (70.6 mg, 2.272 mmol) and sodium 2-methylpropan-2-olate (437mg, 4.54 mmol) in THF (5 mL) was added Pd₂dba₃ (69.3 mg, 0.076 mmol) anddicyclohexyl(2′,4′,6′-triisopropyl-[1,1′-biphenyl]-2-yl)phosphine (36.1mg, 0.076 mmol). The reaction mixture was stirred at 60° C. for 15 h.The mixture was cooled and diluted with water (10 mL). After the mixturewas extracted with EtOAc (10 mL×3), the combined organic fractions werewashed with water (20 mL×3), dried (anhydrous Na₂SO₄), filtered andconcentrated under reduced pressure. The residue was purified byprep-TLC (1/1 petroleum ether/EtOAc) to give the title compound. MS: 215(M+1).

Intermediate W is prepared according to scheme W beginning withcommercial diol W-1. A one-pot oxidation, cyclization, and reductionsequence results in the formation of bromide W-2. A palladium-catalyzedhydroxylation provides intermediate W.

Intermediate W

5,7-Dihydrofuro[3,4-b]pyridin-3-ol (Scheme W) Step 1:3-Bromo-5,7-dihydrofuro[3,4-b]pyridine

TFA (35.3 mL, 459 mmol) was added to a stirred mixture of(5-bromopyridine-2,3-diyl)dimethanol (10 g, 45.9 mmol) in DCM (100 mL)to form a homogeneous solution. Manganese dioxide (18.76 g, 183 mmol)was added to the reaction and the mixture was stirred for 10 min at RTbefore the addition of triethylsilane (14.65 mL, 92 mmol). Afterstirring for 4 h at RT, the reaction was filtered and concentrated. Theresidue was purified by column chromatography on silica gel (10/1EtOAc/hexane) to yield the title compound.

Step 2: 5,7-Dihydrofuro[3,4-b]pyridin-3-ol

KOH (841 mg, 15.0 mmol) in water (10 mL) was added to a stirred mixtureof 3-bromo-5,7-dihydrofuro[3,4-b]pyridine (500 mg, 2.50 mmol),tris(dibenzylideneacetone)dipalladium-chloroform adduct (388 mg, 0.375mmol) and BrettPhos (403 mg, 0.750 mmol) in dioxane (10 mL). Thereaction was stirred at 150° C. under microwave irradiation for 30 min.After cooling to RT, the reaction was partitioned and the lower layerwas separated and concentrated. The residue was purified by columnchromatography on silica gel (20/1 DCM/MeOH) to yield the titlecompound. ¹H NMR (500 MHz, CDCl₃): δ 7.81 (1H, s), 6.94-6.99 (2H, m),6.88 (1H, d, J=8.3 Hz), 6.24 (1H, s), 4.69 (2H, s), 4.57 (1H, m), 4.37(2H, s), 3.58 (2H, m), 3.20 (2H, m), 2.37 (3H, s), 2.14 (2H, m), 1.98(2H, m).

Intermediate X is prepared according to scheme X from an S_(N)Arreaction of a commercial alcohol with 5-bromo-2-fluoropyridine.

Intermediate X1

5-Bromo-2-((1-((tert-butyldiphenylsilyl)oxy)propan-2-yl)oxy)pyridine(Scheme X)

To a solution of 1-((tert-butyldiphenylsilyl)oxy)propan-2-ol (9.83 g,31.3 mmol) in THF (50 mL) was added LHMDS (1 M in THF, 31.3 mL, 31.3mmol) dropwise at 0° C. under a nitrogen atmosphere. After stirring for20 min, 5-bromo-2-fluoropyridine (5 g, 28.4 mmol) in THF (5 mL) wasadded to the reaction. The reaction was allowed to warm to RT and washeated to 70° C. and stirred for 24 h. The reaction was quenched withsaturated, aqueous NH₄Cl (10 mL) and partitioned with water (50 mL) andEtOAc (50 mL×3). The combined organic layers were dried over anhydrousNa₂SO₄, filtered and concentrated. The residue was purified by silicagel chromatography (0-25% EtOAc in petroleum ether) to give the titlecompound. MS: 470, 472 (M+1).

The following intermediates in table X were prepared according to schemeX using the procedure outlined in the synthesis of intermediate X1 usingknown alcohols.

TABLE X Intermediate Structure Name MS (M + 1) X2

5-bromo-2-(2-((tert- butyldiphenylsilyl)oxy) propoxy)pyridine 470, 472

Intermediate Y is prepared according to scheme Y from the reduction of acommercial acid Y-1. Alcohol Y-2 is transformed into intermediate Yafter exposure to mesyl or tosyl chloride in the presence of base.

Intermediate Y1

Bicyclo[1.1.1]pentan-1-ylmethyl methanesulfonate (Scheme Y) Step 1:Bicyclo[1.1.1]pentan-1-ylmethanol

To a solution of bicyclo[1.1.1]pentane-1-carboxylic acid (250 mg, 2.230mmol) in THF (1 mL) was added LiAlH₄ (127 mg, 3.34 mmol) at 0° C. Thereaction was allowed to warm to RT and was stirred for 1 h beforequenching with water (0.25 mL) and anhydrous Na₂SO₄ (1 g). Afterstirring for 20 min, the mixture was filtered and washed with THF. Thecrude solution was used directly in the next step without furtherpurification.

Step 2: Bicyclo[1.1.1]pentan-1-ylmethyl methanesulfonate

To a solution of bicyclo[1.1.1]pentan-1-ylmethanol (219 mg, 0.00 mmol)and Et₃N (0.933 mL, 6.69 mmol) in THF (2 mL) was added Ms-Cl (0.348 mL,4.46 mmol) at 0° C. The reaction was allowed to warm to RT and wasstirred for 15 h. The mixture was treated with water (2 mL) andextracted with EtOAc (10 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by prep-TLC (5/1 petroleum ether/EtOAc) to yield the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 4.13 (2H, s), 3.00 (3H, s), 2.56(1H, s), 1.83 (6H, s).

The following intermediates in table Y were prepared according to schemeY using the procedure outlined in the synthesis of intermediate Y. Incases where the alcohol is commercially available, the first step isomitted.

TABLE Y Inter- MS mediate Structure Name (M + 1) Y2

(2,2-difluoro-1- methylcyclopropyl) methyl 4- methylbenzenesulfonate 277Y3

((trans)-2- (trifluoromethyl)cyclo- propyl)methyl- methanesulfonate 295Y4

2-(1- methylcyclopropyl) ethyl 4- methylbenzenesulfonate 255

Intermediate Z is prepared according to scheme Z from a base-mediatedalkylation of a commericial heterocycle Z-1 (wherein Ar is an aromaticor heteroaromatic ring of R¹).

Intermediate Z1

5-Chloro-3-methyl-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-pyrazolo[3,4-b]pyridine(Scheme Z)

To a solution of compound 5-chloro-3-methyl-1H-pyrazolo[3,4-b]pyridine(200 mg, 1.193 mmol) in THF (3 mL) was added NaH (60%, 52.5 mg, 1.31mmol) at 0° C. After 30 min, SEM-Cl (0.254 mL, 1.432 mmol) was added tothe mixture at 0° C. and the reaction was allowed to warm and stir at RTfor 16 h. The mixture was diluted with saturated NH₄Cl (aq) andextracted with EtOAc (3×10 mL). The combined organic layers were washedwith brine and dried over anhydrous Na₂SO₄ before being concentrated todryness. The residue was purified by silica gel chromatography (0-10%EtOAc in petroleum ether) give the title compound. MS: 298 (M+1).

The following intermediates in table Z were prepared according to schemeZ using the procedure outlined in the synthesis of intermediate Z1 usinga commercial or known reagents.

TABLE Z Intermediate Structure Name MS (M + 1) Z2

5-bromo-2-methyl-1- ((2- (trimethylsilyl)ethoxy) methyl)-1H-benzo[d]imidazole 341, 343 Z3

5-bromo-2-((2- methoxyethoxy)methyl) pyridine 246, 248 Z4

5-bromo-2-methoxy- 2,3-dihydro-1H-indene NMR data¹ Z5²

3-bromo-7-((tert- butyldimethylsilyl)oxy)- 6,7-dihydro-5H-cyclopenta[b]pyridine 329 Z6

5-chloro-1-((2- (trimethylsilyl)ethoxy) methyl)-1H-benzo[d][1,2,3]triazole 284 ¹¹H NMR (400 MHz, CDCl₃): δ 7.33 (1 H, s),7.26 (1 H, s), 7.06 (1 H, d, J = 7.6 Hz), 4.19-4.23 (1 H, m), 3.34 (3 H,s), 3.03-3.15 (2 H, m), 2.91-2.98 (2 H, m). ²Starting bromide may beprepared according to literature procedures, see e.g.: Bara, et al., PCTPatent Publ'n WO2015/084692.

Intermediate AA is prepared according to scheme AA from a base-mediatedalkylation of a commericial indane AA-1.

Intermediate AA

2-(Benzyloxy)-5-bromo-2,3-dihydro-1H-indene (Scheme AA)

To a solution of NaH (60%, 160 mg, 3.99 mmol) in dry THF (5 mL) at 0° C.was added a solution of 5-bromo-2,3-dihydro-1H-inden-2-ol (500 mg, 2.347mmol) in dry THF (5 mL). The resulting solution was stirred for 30 minat 0° C. Benzyl bromide (0.335 mL, 2.82 mmol) was added and the solutionwas stirred at 25° C. for 15 h. The mixture was quenched by saturated,aqueous ammonium chloride (10 mL), which was extracted with EtOAc (40mL×3). The combined organic layers were washed by brine (15 mL×3) andconcentrated to give the crude product, which was purified by silica gelchromatography (1:0-10:1 petroleum ether: EtOAc) to afford the titlecompound. ¹H NMR (400 MHz, CDCl₃): δ 7.25-7.37 (7H, m), 7.07 (1H, d,J=8.0 Hz), 4.57 (2H, s), 4.38-4.47 (1H, m), 2.95-3.23 (4H, m).

Intermediate BB is prepared according to scheme BB from preparedintermediate K16 which was reacted with triethylamine trihydrofluorideto yield trans-fluorobromination product BB-1. Elimination with a strongbase provides allyl fluoride BB-2, which subjected tochlorocyclopanation reaction conditions to give BB-3. Deprotection ofthe piperidine provides BB-4 and a subsequent reduction providesintermediate BB.

Intermediate BB

4-((1-Fluorocyclopropyl)methoxy)piperidine (Scheme BB) Step 1: Benzyl4-(3-bromo-2-fluoropropoxy)piperidine-1-carboxylate

To a solution of benzyl 4-(allyloxy)piperidine-1-carboxylate (4.2 g,15.3 mmol) in DCM (100 mL) was added NBS (4.07 g, 22.9 mmol). At 0° C.,triethylamine trihydrofluoride (9.84 g, 61 mmol) was added dropwise tothe mixture before warming to RT and stirring for 16 h. The reactionmixture was quenched with water (100 mL) and extracted with DCM (3×100mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate and concentrated. The resultant residue waspurified by silica gel chromatography (0-20% EtOAc in petroleum ether)to give the title compound.

Step 2: Benzyl 4-((2-fluoroallyl)oxy)piperidine-1-carboxylate

To a solution of benzyl4-(3-bromo-2-fluoropropoxy)piperidine-1-carboxylate (18 g, 48.1 mmol) inTHF (100 mL) was added potassium 2-methylpropan-2-olate (5.40 g, 48.1mmol) at 0° C. The mixture was stirred at 20° C. for 16 h beforequenching with water (100 mL). The mixture was extracted with EtOAc(3×100 mL) and the combined organic layers were washed with brine, driedover anhydrous sodium sulfate and concentrated. The resultant residuewas purified by silica gel chromatography (0-20% EtOAc in petroleumether) to give the title compound.

Step 3: Benzyl4-((2,2-dichloro-1-fluorocyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of benzyl 4-((2-fluoroallyl)oxy)piperidine-1-carboxylate(1.5 g, 5.11 mmol) in CCl₃ (15 mL) was addedN-benzyl-N,N-dibutylbutan-1-aminium chloride (0.160 g, 0.511 mmol). Anaqueous sodium hydroxide (50%, 1.64 g, 20.45 mmol) was added dropwise tothe mixture at 0° C. and the mixture was stirred at 15° C. for 16 h. Thereaction was quenched by water (20 mL) and partitioned with DCM (3×10mL). The combined organic layers were washed with brine, dried overanhydrous sodium sulfate, filtered and concentrated. The resultantresidue was purified by silica gel chromatography (0-50% EtOAc inpetroleum ether) to give the title compound.

Step 4: 4-((2,2-Dichloro-1-fluorocyclopropyl)methoxy)piperidine

A solution of benzyl4-((2,2-dichloro-1-fluorocyclopropyl)methoxy)piperidine-1-carboxylate(600 mg, 1.595 mmol) in THF (30 mL) with Pd/C (16.97 mg, 0.159 mmol) wasstirred at 40° C. for 2 h under an atmosphere of hydrogen. The reactionmixture was filtered and concentrated to give the crude title compound,which was carried forward without purification.

Step 5: 4-((1-Fluorocyclopropyl)methoxy)piperidine

To a solution of compound4-((2,2-dichloro-1-fluorocyclopropyl)methoxy)piperidine (300 mg, 1.239mmol) in THF (2 mL) was added LiAlH₄ (188 mg, 4.96 mmol) at 0° C. Afterstirring for 4 hr at 15° C., additional LiAlH₄ (188 mg, 4.96 mmol) wasadded. The reaction was stirred for 16 h before quenching with water(0.3 mL) and filtering off insolubles. The filtrate was concentrated toprovide the title compound. MS: 174 (M+1).

Intermediate CC is prepared according to scheme CC from preparedintermediate K2 which was reacted with the Ruppert-Prakash reagent inthe presence of sodium iodide to yield cyclopropyl adduct CC-1.Deprotection of the piperidine provides intermediate CC.

Intermediate CC

4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidine (Scheme CC) Step1: Benzyl4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

Sodium iodide (200 mg, 1.33 mmol) was added to a solution of benzyl4-((2-methylallyl)oxy)piperidine-1-carboxylate (1.163 g, 4.02 mmol) inTHF (9 mL) under a nitrogen atmosphere in a pressure vessel.(Trifluoromethyl)trimethylsilane (2.0 mL, 14.1 mmol) was added, thereaction was sealed and was stirred at 65° C. for 15 h. Volatiles wereremoved under reduced pressure and the residue was purified by silicagel chromatography (5-35% EtOAc in hexanes) to provide the titlecompound.

Step 2: 4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidine

Benzyl4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(1.174 g, 3.46 mmol) was dissolved in MeOH (11.5 mL). The flask wasevacuated and charged with nitrogen, then Pd/C (20%, 0.243 g, 0.346mmol) was added to the solution and placed under an atmosphere ofhydrogen. After stirring for 2 h, the mixture was filtered throughcelite and concentrated to provide the title compound. MS: 206 (M+1).

Intermediate DD is prepared according to scheme DD from known arylcompound DD-1 which was borylated via C—H activation using an iridiumcatalyst.

Intermediate DD

4,4,5,5-tetramethyl-2-(1,2,4,5-tetrahydrobenzo[d]oxepin-7-yl)-1,3,2-dioxaborolane(Scheme DD)

To a solution of 1,2,4,5-tetrahydrobenzo[d]oxepine (100 mg, 0.675 mmol)(for synthesis of this compound, see e.g. Pehlivan, M. Eur. J. Org.Chem. 2012, 25, 4689-4693) and Bis(pinacolato)diboron (274 mg, 1.080mmol) in dioxane (3 mL) was added (1,5-cyclooctadiene)(methoxy)iridium(I) dimer (44.7 mg, 0.067 mmol) and 4,4′-di-tert-butyl-2,2′-bipyridine(36.2 mg, 0.135 mmol) (18.11 mg, 0.067 mmol). The mixture was stirred at100° C. for 16 h under an inert atmosphere. The volatiles were removedunder reduced pressure and the residue was purified by silica gelchromatography (8-10% THF in petroleum ether) to give the titlecompound. MS: 275 (M+1).

The following intermediates in table DD were prepared according toscheme DD using the procedure outlined in the synthesis of intermediateDD1 using a commercial or known reagents.

TABLE DD Intermediate Structure Name MS (M + 1) DD2¹

6-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2- yl)-2,3- dihydrofuro[3,2-b]pyridine 248 ¹Heteroarene may be prepared according to literatureprocedures, see e.g.: Hayakawa, I.; et al. Chem. Pharm. Bull. 1984, 32,4914-4922.

Intermediate EE is prepared according to scheme EE from preparedpiperidine K-2 which was reacted with ethyl diazoacetate in the presenceof rhodium(II) acetate to yield cyclopropyl adduct EE-1. Saponificationto acid EE-2 and subsequent coupling reaction with ammonium chlorideprovides amide EE-3. Dehydration provides corresponding nitrile EE-4which after deprotection of the piperidine provides intermediate EE.

Intermediate EE

2-Methyl-2-((piperidin-4-yloxy)methyl)cyclopropane-1-carbonitrile(Scheme EE) Step 1: tert-Butyl4-((2-(ethoxycarbonyl)-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a mixture of tert-butyl4-((2-methylallyl)oxy)piperidine-1-carboxylate (1.02 g, 4.0 mmol) andrhodium(II) acetate (88.4 mg, 0.2 mmol) in DCM (5 mL) was added asolution of ethyl diazoacetate (502 mg, 4.4 mmol) in DCM (10 mL)dropwise at 0° C. over 4 h. The reaction mixture was warmed to RT andstirred for 50 h. The volatiles were removed under reduced pressure andthe residue was purified by a silica gel column chromatography (5:1petroleum ether:EtOAc) to afford the title compound.

Step 2:2-(((1-(tert-Butoxycarbonyl)piperidin-4-yl)oxy)methyl)-2-methylcyclopropane-1-carboxylicAcid

To a solution of tert-butyl4-((2-(ethoxycarbonyl)-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(512 mg, 1.5 mmol) in THF (5 mL) was added a solution of lithiumhydroxide (126 mg, 3.0 mmol) in water (1 mL). The reaction mixture washeated to 40° C. for 15 h and was cooled to RT before adjusting the pH˜3with an aqueous HCl solution and partitioning with DCM (3×30 mL). Thecombined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated to dryness to yield the title compound.

Step 3: tert-Butyl4-((2-carbamoyl-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((2-(ethoxycarbonyl)-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(313 mg, 1.05 mmol) in DCM (10 mL) and triethylamine (320 mg, 3.15 mmol)was added HATU (598 mg, 1.58 mmol). The reaction mixture was stirred for10 min before ammonium chloride (84 mg, 1.58 mmol) was added at RT.After stirring for 15 h, the reaction was diluted with water (10 mL) andextraced with DCM (3×30 mL). The combined organic layers were dried overanhydrous sodium sulfate, filtered and concentrated to dryness. Theresultant residue was purified by a silica gel column chromatography(10:1 DCM: MeOH) to afford the title compound.

Step 4: tert-Butyl4-((2-cyano-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((2-carbamoyl-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(320 mg, 1.02 mmol) in THF (5 mL) was added pyridine (324 mg, 4.1 mmol)at 0° C. The reaction mixture was stirred for 10 min before TFAA (514mg, 2.4 mmol) was added. The system was gradually warmed to RT and wasstirred 15 h, before removing volatiles under reduced pressure. Theresultant residue was purified by a silica gel column chromatography(2:1 petroleum ether:EtOAc) to afford the title compound.

Step 5:2-Methyl-2-((piperidin-4-yloxy)methyl)cyclopropane-1-carbonitrile

To a solution of tert-butyl4-((2-cyano-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate in DCM(10 mL) was added TFA (1 mL, 13.4 mmol) at 0° C. The reaction wasstirred for 15 h before the volatiles were removed under reducedpressure to provide the title compound. MS: 195 (M+1).

Intermediate FF is prepared according to scheme FF from prepared orknown piperidine FF-1 which was reacted with an akyl halide in thepresence of base to provide alkyl adduct FF-2. Deprotection of thepiperidine provides intermediate FF.

Intermediate FF

1-((Piperidin-4-yloxy)methyl)cyclopropan-1-ol (Scheme FF) Step 1: Benzyl4-((1-methoxycyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of benzyl4-((1-hydroxycyclopropyl)methoxy)piperidine-1-carboxylate (100 mg, 0.327mmol) in THF (3 mL) was added NaH (60%, 26.2 mg, 0.655 mmol) at 0° C.After 30 min, MeI (0.29 mL, 4.65 mmol) was added at 0° C. and thereaction was stirred for 12 h at RT. The mixture was quenched bysaturated aqueous ammonium chloride (5 mL), extracted with EtOAc (3×15mL). The combined organic layers were washed by brine (10 mL) andconcentrated to afford the title compound.

Step 2: 1-((Piperidin-4-yloxy)methyl)cyclopropan-1-ol

To a solution of benzyl4-((1-methoxycyclopropyl)methoxy)piperidine-1-carboxylate (100 mg, 0.313mmol) in MeOH (5 mL) was added Pd/C (10%, 16.7 mg, 0.157 mmol). Thereaction was placed under a hydrogen atmosphere (40 psi) for 3 h at 20°C. for 3 h. The mixture was filtered and the residue was concentrated togive title compound. ¹H NMR (400 MHz, CDCl3): δ 7.79 (1H, s), 6.12 (1H,br s), 4.35 (2H, s), 3.63 (2H, s), 3.54-3.59 (3H, m), 3.39 (3H, s), 3.03(2H, t, J=10.0 Hz), 2.34 (3H, s), 2.03-2.07 (2H, m), 1.74-1.83 (2H, m),0.83-0.88 (2H, m), 0.58-0.63 (2H, m).

Intermediate GG is prepared from a known or commercial halide GG-1 whichis transformed to the corresponding boronic ester GG-1 via a Miyauraborylation reaction. Oxidation provides the phenol GG-3 whichparticipates in a diplacement reaction with sulfone GG-2 to provideadduct GG-4. Deprotection under acidic or reductive conditions providesintermediate GG.

Intermediate GG1

5-(Piperidin-4-yloxy)-2,3-dihydrofuro[2,3-b]pyridine (Scheme GG) Step 1:5-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-b]pyridine

To a solution of 5-bromo-2,3-dihydrofuro[2,3-b]pyridine (80 mg, 0.400mmol) (for synthesis of this compound, see e.g. Martin, R., et. al. Eur.J. Org. Chem. 2012, 47-52), bis(pinacolato)diboron (122 mg, 0.480 mmol)and potassium acetate (98 mg, 1.00 mmol) in dioxane (2 mL) was addedPdCl₂(dppf) (29.3 mg, 0.040 mmol). After addition, the mixture wasplaced under a nitrogen atmosphere and was heated to 80° C. for 16 h.The mixture was concentrated, diluted with EtOAc (20 mL) and washed bywater (20 mL). The organic phase was dried over anhydrous sodiumsulfate, filtered and concentrated to afford the title compound.

Step 2: 2,3-Dihydrofuro[2,3-b]pyridin-5-ol

To a solution of5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydrofuro[2,3-b]pyridine(120 mg, 0.243 mmol) in MeOH (3 mL) was added hydrogen peroxide (30%, 1mL, 9.79 mmol). After stirring for 1 h at RT, the mixture was quenchedwith saturated aqueous sodium thiosulfate (10 mL) and diluted with EtOAc(15 mL). The organic phase was dried over anhydrous sodium sulfate,filtered and concentrated to afford the title compound.

Step 3: tert-Butyl4-((2,3-dihydrofuro[2,3-b]pyridin-5-yl)oxy)piperidine-1-carboxylate

To a solution of 2,3-dihydrofuro[2,3-b]pyridin-5-ol (80 mg, 0.58 mmol),tert-butyl4-(((4-(trifluoromethyl)phenyl)sulfonyl)oxy)piperidine-1-carboxylate(358 mg, 0.88 mmol) in DMF (5 mL) was added cesium carbonate (570 mg,1.75 mmol). After stirring at 75° C. for 16 h, the mixture was dilutedwith water (15 mL) and extracted by EtOAc (3×10 mL). The combinedorganic phases were washed by water (3×10 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography (0-35% EtOAc in petroleum ether) to give thetitle compound.

Step 4: 5-(Piperidin-4-yloxy)-2,3-dihydrofuro[2,3-b]pyridine

To a solution of tert-butyl4-((2,3-dihydrofuro[2,3-b]pyridin-5-yl)oxy)piperidine-1-carboxylate (65mg, 0.203 mmol) in DCM (2 mL) was added TFA (0.2 mL, 2.60 mmol). Afteraddition, the mixture was stirred at 20° C. for 15 min. The mixture wasconcentrated to afford the title compound. MS: 221 (M+1).

The following intermediates in table GG were prepared according toscheme GG using the procedure outlined in the synthesis of intermediateGG1 using a commercial or known reagents.

TABLE GG Intermediate Structure Name MS (M + 1) GG2

4-((2-methoxy-2,3- dihydro-1H-inden-5- yl)oxy)piperidine 248 GG3

5-(piperidin-4-yloxy)- 1H- benzo[d][1,2,3]triazole 219

Intermediate HH is prepared under oxidative conditions to provideintermediate GG_from a known or available thioether HH-1.

Intermediate HH

5-Bromo-1,3-dihydrobenzo[c]thiophene 2-oxide (Scheme HH)

To a solution of compound 5-bromo-1,3-dihydrobenzo[c]thiophene (731 mg,3.40 mmol) in DCM (10 mL) was added m-CPBA (1005 mg, 4.08 mmol) at 0° C.After stirring for 1 h at RT, the mixture was quenched with aqueous,saturated Na₂SO₃ (20 mL) and partitioned with DCM (10 mL×3). Thecombined organic layers were washed with brine, dried over anhydroussodium sulfate and concentrated. The residue was purified by silica gelchromatography (0-100% THF in petroleum ether) to yield the titlecompound. MS: 231, 233 (M+1).

Intermediate II is prepared by an S_(N)Ar reaction of commericiallyavailable piperidinol II-1 with prepared 2-chloropyridine II-2 toprovide intermediate II.

Intermediate II1

Methyl2-cyano-6-(3,3-difluoro-4-hydroxypiperidin-1-yl)-5-ethylnicotinate(Scheme II)

To a solution of 3,3-difluoropiperidin-4-ol (HCl salt, 73.8 mg, 0.383mmol) in dry DMF (2 mL) was added methyl6-chloro-2-cyano-5-ethylnicotinate (43 mg, 0.191 mmol) and DIPEA (74.2mg, 0.574 mmol). The mixture was stirred at 80° C. for 15 h under aninert atmosphere. The reaction was cooled to RT and was treated withwater (10 mL) and extracted with EtOAc (10 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated to dryness. The residue was purified by silica gelchromatography (0-50% EtOAc in petroleum ether) to give the titlecompound. MS: 326 (M+1).

The following intermediates in table II were prepared according toscheme II using the procedure outlined in the synthesis of intermediateII1.

TABLE II Inter- MS mediate Structure Name (M + 1) II2

methyl 2-cyano-6-(4- hydroxypiperidin-1-yl)- 4,5-dimethylnicotinate 290

Intermediate JJ is prepared by exposure of intermediate II tohydrogenation conditions to elicit lactam formation.

Intermediate JJ

2-(4-Hydroxypiperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme JJ)

To methyl 2-cyano-6-(4-hydroxypiperidin-1-yl)-4,5-dimethylnicotinate(intermediate II2, 275 mg, 0.950 mmol) in EtOH (9505 μL) and AcOH (272μL, 4.75 mmol) was added Pd/C (10 wt %, 101 mg, 0.095 mmol). The systemwas evacuated and flushed with nitrogen 3 times before placing under anatmosphere of hydrogen. After stirring for 15 h, the reaction wasfiltered and the volatiles were removed under reduced pressure. Theresidue was diluted in TEA (0.5 mL) and MeOH (5 mL) and stirred at RTfor 8 h. The mixture was filtered over celite and filtrate wasconcentrated to provide the title compound. MS: 262 (M+1).

Intermediate KK is prepared by exposure of intermediate K2 todibromofluoromethane to obtain cyclopropane KK-1. ydrogenationconditions to elicit lactam formation.

Intermediate KK

2-(4-Hydroxypiperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme JJ) Step 1: Benzyl4-((2-bromo-2-fluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of benzyl 4-((2-methylallyl)oxy)piperidine-1-carboxylate(intermediate K2, 500 mg, 1.73 mmol) in DCM (5 mL) and water (0.5 mL)was added NaOH (346 mg, 8.64 mmol) and N-benzyl-N,N-diethylethanaminiumchloride (5.90 mg, 0.026 mmol) and dibromofluoromethane (497 mg, 2.59mmol). After stirring at 50° C. for 20 h, the reaction was treated withwater (5 mL) and extracted with DCM (25 mL×3). The combined organiclayers were dried over anhydrous sodium sulfate, filtered andconcentrated. The resultant residue was purified by silica gelchromatography (0-40% EtOAc/petroleum ether) to give the title compound.

Step 2: Benzyl4-((2-fluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate

To a solution of benzyl4-((2-bromo-2-fluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate(150 mg, 0.375 mmol) in EtOH (5 mL) was added zinc (49.0 mg, 0.749 mmol)and ammonium chloride (60.1 mg, 1.124 mmol). The reaction was stirred at70° C. for 8 h. The mixture was filtered, concentrated and diluted withwater (10 mL) and extracted with EtOAc (15 mL×3). The organic layerswere concentrated to dryness to afford the title compound.

Step 3: 4-((2-Fluoro-1-methylcyclopropyl)methoxy)piperidine

To a solution of benzyl4-((2-fluoro-1-methylcyclopropyl)methoxy)piperidine-1-carboxylate (300mg, 0.933 mmol) in EtOH (10 mL) was added Pd/C (10 wt %, 99 mg, 0.933mmol) under a nitrogen atmosphere. The reaction was stirred at RT for 2h under a hydrogen atmosphere before the mixture was filtered andconcentrated to provide the title compound. MS: 188 (M+1).

Intermediate LL is prepared via an nucleophilic electrophilic epoxideopening reaction between commercially available piperidine LL-1 andphenol to afford adduct LL-2. Oxidation of alcohol LL-2 provides ketoneLL-3, which is subsquently reacted with DAST to give the correspondingdifluoro product LL-4. Acid-mediated deprotection of N-Boc piperidineprovides intermediate LL.

Intermediate LL

3,3-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine (Scheme LL)Step 1: tert-Butyl3-hydroxy-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine-1-carboxylate

A mixture of tert-butyl 7-oxa-3-azabicyclo[4.1.0]heptane-3-carboxylate(1.2 g, 6.02 mmol), 1-methyl-1H-pyrazol-4-ol (0.768 g, 7.83 mmol) andcesium carbonate (2.94 g, 9.03 mmol) in DMF (15 mL) was stirred at 80°C. for 16 h. The mixture was cooled to RT dissolved in EtOAc (100 mL),washed with water (100 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The curde material was purified by silica gelchromatography (1/1 petroleum ether/THF) to give the title compound.

Step 2: tert-Butyl4-((1-methyl-1H-pyrazol-4-yl)oxy)-3-oxopiperidine-1-carboxylate

A solution of tert-butyl3-hydroxy-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine-1-carboxylate (1.2g, 4.04 mmol) and DMP (5.14 g, 12.1 mmol) in DCM (20 mL) was stirred at25° C. for 16 h. The mixture was filtered and the filtrate wasconcentrated before purification by silica gel chromatography (1/1petroleum ether/THF) to give the title compound.

Step 3: tert-Butyl3,3-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine-1-carboxylate

To a solution of tert-butyl4-((1-methyl-1H-pyrazol-4-yl)oxy)-3-oxopiperidine-1-carboxylate (800 mg,2.71 mmol) in DCM (10 mL) was added DAST (1.79 mL, 13.5 mmol). Thereaction was stirred at RT for 16 h before it was carefully poured intoaqueous NaHCO₃ (saturated, 30 mL). After extracting with DCM (50 mL),the organic layer was washed with water (30 mL), dried over anhydroussodium sulfate, filtered and concentrated. Purification by silica gelchromatogrpahy (70:30 petroleum ether: THF) afforded the title compound.

Step 4: 3,3-Difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine

To a solution of tert-butyl3,3-difluoro-4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidine-1-carboxylate(100 mg, 0.315 mmol) in dioxane (0.5 mL) was added hydrogen chloride (4M in dioxane, 1 mL, 4.00 mmol). The reaction was stirred at RT for 1 hrand the volatiles were then removed under reduced pressure to afford thetitle compound. MS: 218 (M+1).

Compounds of formula (I) are synthesized from an S_(N)Ar reaction ofprepared 2-chloro pyridines 1-1, and commericially available or preparedpiperidines 1-2.

Compounds of formula (I) are synthesized from a Mitsunobu reaction usingtriphenyl phosphine and an azodicarboxylate with a known or preparedphenol 2-2 and prepared alcohol 2-1.

Compounds of formula (I) are synthesized from a Mitsunobu reaction usingtriphenyl phosphine and an azodicarboxylate with a known or preparedphenol 3-2 associated with a protecting group and prepared alcohol 3-1.Subsequent deprotection of adduct 3-3 is accomplished with exposure toacid or TBAF to provide compound (I).

Compounds of formula (I) are synthesized from a Mitsunobu reaction usingtriphenyl phosphine and an azodicarboxylate with a known or preparedphenol 4-2 associated with a pendant carbonyl group and prepared alcohol4-1. Subsquent reduction of carbonyl 4-3 with a metal hydride providescompound (I).

Compounds of formula (I) are synthesized from an S_(N)Ar of preparedpyridine 5-1 and a known or prepared piperdine 5-2. Reduction of nitrile5-3 can be carried out with a platinum, or palladium, or nickel-basedcatalyst or else a metal borohydride reagent such that the resulantamine cyclizes to form a lactam often in the presence of base. In caseswhere stereocenter(s) are present, additional chiral resolution ofisomers may be carried out.

Compounds of formula (I) are synthesized from prepared nitrile 6-1 via aS_(N)Ar reaction with a known or prepared piperdine 6-2 to provideadduct 6-3. Reduction of intermediate 6-3 can be carried out with apalladium or nickel catalyst, wherein the amine will cyclize to form thelactam often in the presence of base to yield compound 6-4.Electrophilic bromination with NBS cleanly provides bromide 6-5 which iselaborated via a palladium-mediated Suzuki or Negishi reaction to formcompound (I).

Compounds of formula (I) are synthesized via the reduction of olefin 7-1by palladium-mediated hydrogenation.

Compounds of formula (I) are synthesized from bromide 8-1 viacopper-mediated trifluoromethylation.

Compounds of formula (I) are synthesized via the alkylation of thelactam 9-1 with an alkyl halide or mesylate in the presence of a basesuch as LHMDS or NaH. Under reaction conditions using an equivalent ofbase, the major observed product is adduct 9-2 and in some cases theformation of the overalkylation product 9-3. Under reaction conditionsusing an excess of base, the major observed product is adduct 9-4. Incases where the added moiety contains a silyl protecting group, TBAF isused to unmask the alcohol to provide compound (I).

Compounds of formula (I) are synthesized from lactam 10-1, which istransformed to 10-2 via an alkylation with methyl 2-bromoacetate aftertreatment with base. Two conditions were used to provide compounds ofthe formula (I), either saponification followed by reduction of thecarboxylic acid with a hydride source or direct reduction of the esterwith a borohydride. In cases where the added moiety contains astereocenter, chiral resolution of the enantiomers may be carried out.

Compounds of formula (I) are synthesized from lactam 11-1 through aChan-Lam coupling reaction.

Compounds of formula (I) are synthesized from lactam 12-1 through aninitial SEM-protection reaction to provide intermediate 12-2.1-Hydroxymethylbenzotriazole is used for the in situ generation ofanhydrous formaldehyde in the presence of the base to provide adduct12-4. In some cases, the SEM group was found to form hydroxymethyl 12-3as a by-product under the reaction condition. Deprotection of lactam12-4 is accomplished using TBAF or TFA to provide 12-5. Chiralresolution is carried out by SFC to provide compounds of the formula(I).

Compounds of formula (I) are synthesized from lactam 13-1 by an in situgeneration of anhydrous formaldehyde in the presence of the base toprovide adduct 13-2. Chiral resolution is carried out by SFC to providecompounds of the formula (I).

Compounds of formula (I) are synthesized from lactam 14-1 by abase-mediated alkylation with a commercial alkyl halide. Chiralresolution is carried out on adduct 14-2 by SFC to provide compounds ofthe formula (I).

Compounds of formula (I) are synthesized from lactam 15-1 through anbase-mediated alkylation with a commercial alkyl halide that can giverise to a mono- and bis-adduct, 15-2 and 15-3, respectively. TBAF isused to deprotect the lactam in cases where the 15-2 or 15-3 includes asilyl protecting group.

Compounds of formula (I) are synthesized from alcohol 12-3 through anbase-mediated elimination reaction. Deprotection of lactam 16-1 isaccomplished using TFA to provide compounds of formula (I).

Compounds of formula (I) are synthesized from amine 17-1 through areductive amination reaction with a commercially available aldehyde.

Compounds of formula (I) are synthesized from amine 18-1 through anacylation with a commercially available acyl chloride.

Compounds of formula (I) are synthesized from intermediate 5-3 (fromscheme 5) which is saponified to carboxylate 19-1. Under couplingconditions with a commercially available amine, adduct 19-2 andcompounds of the formula (I) are obtained. Saponification of nitrile19-2 gives rise to carboxylic acid 19-3, which was carried forward intoan acyl chloride formation with a reductive work-up to yield compoundsof the formula (I).

Compounds of formula (I) are synthesized from lactam 20-1 throughreaction with a commercially available anhydride.

Compounds of formula (I) are synthesized from intermediate 5-3 (fromscheme 5) through a Kulinkovich reaction.

Compounds of formula (I) are synthesized from ester 22-1 which isreduced to the alcohol. Compounds of formula (I) are also prepared froma further reaction of the alcohol with DAST.

Compounds of formula (I) are synthesized from alcohol 23-1 throughoxidation to the aldehyde using Dess-Martin reagent. Compounds offormula (I) are also prepared from a further reaction of the aldehydewith DAST.

Compounds of formula (I) are synthesized from a reduction of nitrile24-1 using DIBAL. Compounds of formula (I) are also prepared from afurther reduction of the aldehyde using other metal hydrides to form thecorresponding alcohol.

Compounds of formula (I) are synthesized from the reaction of ester 25-1with ammonium hydroxide for form the corresponding carboxamide.

Compounds of formula (I) are synthesized from prepared N-protectedpiperidine 26-1 via either an acid-mediated deprotection or reductiveconditions using Pd catalyst in the presence of hydrogen to form amine26-2. A subsequent S_(N)Ar with prepared aryl chloride 26-3 forms adduct26-4. Reduction of nitrile 26-4 can be carried out with a platinum, orpalladium, or nickel-based catalyst such that the resulant aminecyclizes to form a lactam often in the presence of base.

Compounds of formula (I) are synthesized from indazole 27-1 afterreaction with a N-halosuccinimide.

Compounds of formula (I) are synthesized from bromide 28-1 after apalladium-catalyzed Negishi reaction.

Compounds of formula (I) are synthesized from indazole 29-1 afterreaction with Selectfluor.

Compounds of formula (I) are synthesized from a base-mediatedN-alkylation of lactam 30-1 through an epoxide ring-opening reactionwith commercially available epoxides.

Compounds of formula (I) are synthesized from a known or prepared phenolprecursor 31-1 that after treatment under reductive or oxidativereaction conditions reveals phenol 31-2. A Mitsunobu reaction usingtriphenyl phosphine and an azodicarboxylate with prepared alcohol 31-3provides compounds having the formula (I).

Compounds of formula (I) are synthesized from lactam 32-1 through analdol reaction with a commercial aldehyde or ketone.

Compounds of formula (I) are synthesized from an S_(N)Ar reaction ofprepared pyridine 33-1 and a known or prepared piperdine 33-2. Reductionof nitrile 33-3 can be carried out with a platinum, or palladium, ornickel-based catalyst such that the resulant amine cyclizes to form alactam often in the presence of base. A final deprotection step, and insome examples a chiral resolution was carried out to provide compoundshaving the formula (I).

Compounds of formula (I) are synthesized from a base-mediated reactionof lactam 34-1 with chlorophosphate to yield adduct 34-2 followed byphosphodiester hydrolysis.

Compounds of formula (I) are synthesized from ether 35-1 byO-demethylation mediated by trimethylsilyliodide.

Compounds of formula (I) are synthesized beginning from an S_(N)Arreaction of commercial 2-fluoropyridine 36-1 with prepared piperidine36-2. Adduct 36-3 is reacted with NCS to provide the chlorinated product36-4. A second S_(N)Ar reaction with sodium cyanide provides nitrileadduct 36-5. Methylation is carried out in the presence of base toprovide Me-ester 36-6. Reduction of intermediate 36-6 can be carried outwith a palladium or nickel catalyst, wherein the intermediary amine willcyclize to form the lactam often in the presence of base to affordcompound (I).

Compounds of the formula (I) are synthesized from prepared piperidine37-1 and aryl chloride 37-2 to form adduct 37-3 in a S_(N)Ar reaction.Reduction of nitrile 37-3 can be carried out with a platinum, palladiumor nickel-based catalyst and hydrogen, such that the resultant amidecycles to form lactam 37-4, often in the presence of base. A 2-stepprocedure is used to reduce ester 37-4 to compounds of the formula (I)via a borohydride reduction followed by a second reduction usingzinc-dust. In cases where a stereocenter is present in R¹, chiralresolution may be carried out as a final step.

Compounds of formula (I) are synthesized from a base-mediated alkylationof lactam 38-1 with an alkyl halide to yield adduct 38-2. Hydroxylationby the in situ generation of anhydrous formaldehyde in the presence ofbase and subsequent chiral resolution provide compounds of the formula(I).

Compounds of formula (I) are synthesized from a reduction of ester 39-1using a metal hydride to form the corresponding alcohol.

Compounds of formula (I) are synthesized from alcohol 40-1 throughoxidation to the aldehyde 40-2 using Dess-Martin reagent and asubsequent Wittig reaction.

Compounds of formula (I) are synthesized from alcohol 41-1 after aDess-Martin periodinane mediated oxidation reaction.

Compounds of the formula (I) are synthesized from a prepared alcoholintermediate II and alkylation to form adduct 42-1. Simmons-Smithreaction conditions provides cyclopropyl adduct 42-2. Reduction ofnitrile 42-2 can be carried out with a platinum, palladium ornickel-based catalyst such that the resultant amide cycles to formcompounds of the formula (I). In cases, where there is a stereocenter,an additional chiral resolution step may be carried out.

Compounds of formula (I) are synthesized via a hydroxylation reaction oflactam 43-1 by the in situ generation of anhydrous formaldehyde in thepresence of base and subsequent reduction of ester 43-2 to providecompounds of the formula (I).

Example 1

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 1)

To a 500 mL flask containing2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (18 g, 99mmol, intermediate B1), 2-methoxy-5-(piperidin-4-yloxy)pyridinedihydrochloride (29.1 g, 104 mmol, intermediate F1) and sodiumbicarbonate (33.1 g, 394 mmol) was added N-methyl-2-pyrrolidinone (246mL). The system was fitted with a condenser and the system was heated to160° C. and was stirred for 15 h. The mixture was cooled to RT andfiltered and the filtrate was partitioned with water (1.5 L) and 1:5EtOAc:DCM (500 mL). The organic layer was washed with 1:1 brine:water(500 mL), dried over anhydrous sodium sulfate, filtered over a small padof celite/silicagel/activated carbon, and concentrated. The residue wasdissolved in hot iPrOH with DCM (˜10%) and the mixture was sonicated andheated to 60° C. for 30 min. After slowly cooling the mixture to RT, thesolids were collected and washed with 1:1:1 ether:iPrOH:heptane and waslyophilized to yield the title compound. MS: 355 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 7.88 (1H, d, J=2.88 Hz), 7.81 (1H, s), 7.27 (1H, t, J=5.56Hz), 6.72 (1H, d, J=8.91 Hz), 6.40 (1H, s), 4.38-4.39 (1H, m), 4.37 (1H,s), 3.91 (3H, s), 3.57 (3H, br s), 3.14-3.18 (2H, m), 2.37 (3H, s), 2.13(2H, br s), 1.94-1.98 (2H, m).

Example 2A and 2B

2-((3R,4R)-4-((6-methoxypyridin-3-yl)oxy)-3-methylpiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand2-((3S,4S)-4-((6-methoxypyridin-3-yl)oxy)-3-methylpiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 1)

A suspension of 2-methoxy-5-((trans-3-methylpiperidin-4-yl)oxy)pyridine(245 mg, 1.10 mmol),2-chloro-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (201 mg,1.10 mmol, intermediate B1) and Hunig's base (384 μL, 2.20 mmol) inN-methyl-2-pyrrolidinone (3 mL) was prepared. The system was sealed andwas heated to 175° C. for 19 h. After cooling, the reaction was dilutedwith EtOAc, washed with water (3×) and brine, dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bymass triggered reverse phase HPLC (ACN/water with 0.1% NH₃OH modifier)to afford the racemate. The mixture of the two stereoisomers wasresolved by chiral SFC (OJ-H column, 15% MeOH/CO₂) to afford isomer 2A(faster eluting): MS: 369 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (1H, d,J=3.0 Hz), 7.83 (1H, s), 7.28-7.30 (1H, m), 6.73 (1H, d, J=8.9 Hz), 6.21(1H, s), 4.38 (2H, s), 3.93 (3H, s), 3.85-3.87 (1H, m), 3.66 (2H, dd,J=12.7, 4.1 Hz), 2.97-3.02 (1H, m), 2.78 (1H, dd, J=13.1, 9.9 Hz), 2.39(3H, s), 2.14-2.23 (2H, m), 1.79-1.86 (1H, m), 1.17 (3H, d, J=6.6 Hz).Isomer 2B (slower eluting): MS: 369 (M+1). ¹H NMR (500 MHz, CDCl₃): δ7.90 (1H, d, J=3.0 Hz), 7.83 (1H, s), 7.28-7.30 (1H, m), 6.73 (1H, d,J=8.9 Hz), 6.21 (1H, s), 4.38 (2H, s), 3.93 (3H, s), 3.85-3.87 (1H, m),3.66 (2H, dd, J=12.7, 4.1 Hz), 2.97-3.02 (1H, m), 2.78 (1H, dd, J=13.1,9.9 Hz), 2.39 (3H, s), 2.14-2.23 (2H, m), 1.79-1.86 (1H, m), 1.17 (3H,d, J=6.6 Hz).

The following examples in table 1 were prepared according to scheme 1using the procedure outlined in the synthesis of Example 1 or Example 2Aand 2B using known or prepared piperidines and 2-chloropyridines.Alternative conditions can be used in this reaction, such that the baseis DIPEA, sodium bicarbonate, or tributylamine as appropriate for eachsubstrate.

TABLE 1 Example Structure Name MS (M + 1)  3

3-((1-(3-methyl-5- oxo-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 349     3A

3-methyl-2-(4- (((trans)-2- (trifluoromethyl) cyclopropyl)methoxy)piperidin-1-yl)-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 370  4

3-methyl-2-(4-((1- methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 378     4A

2-(4- (difluoromethoxy) piperidin-1-yl)-3- methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 298  5

3-methyl-2-(4- phenoxypiperidin- 1-yl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 324     5A

3-ethyl-2-((3S,4R)- 3-fluoro-4-((1- methyl-1H-indazol-5-yl)oxy)piperidin- 1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one410  6

2-((3S,4R)-3- fluoro-4-((1- methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 424     6A

3-ethyl-2-((3S,4S)- 3-fluoro-4-((1- methylcyclopropyl)methoxy)piperidin- 1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one348  7

3-((cis-3-fluoro-1- (3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile 367  8

2-((3S,4R)-4-((1H- indazol-5-yl)oxy)- 3-fluoropiperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 382     8A   8B

(R)-2-(4-((2,2- difluoro-1- methylcyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one and(S)-2-(4-((2,2- difluoro-1- methylcyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 352 352  9

2-(4- (cyclopropylmethoxy) piperidin-1-yl)- 3-methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 302 10

2-(4-((2- cyclopropyl-3- oxoisoindolin-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 419 11

3-((1-(3,6- dimethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 363 12

2-(4-((1H-indazol- 5-yl)oxy)piperidin- 1-yl)-3,6-dimethyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 378 13

3-((1-(3,6,7- trimethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 377 14

2-(4-((1H-indazol- 5-yl)oxy)piperidin- 1-yl)-3,6,7- trimethyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 392 15

3-((1-(3,6,7,7- tetramethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile 391 16

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1- yl)-3,6,7-trimethyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 383 17

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1- yl)-3,6,7,7-tetramethyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 397 18

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1- yl)-3,6-dimethyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 369 19

3-(((3R,4S)-3- fluoro-1-(3-methyl- 5-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile 367 20

3-(((3S,4S)-3- fluoro-1-(3-methyl- 5-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile 367 21

3-(((3R,4R)-3- fluoro-1-(3-methyl- 5-oxo-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile 367 22

3-methyl-2-(4- ((1,2,3,4- tetrahydroquinolin- 6-yl)oxy)piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 379 23

2-((3R,4S)-3- fluoro-4-((1- methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 396 24

2-((3S,4S)-3-fluoro- 4-((1-methyl-1H- indazol-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 396 25

2-((3R,4R)-3- fluoro-4-((1- methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 396 26

2-(4-((1H-indo1-5- yl)oxy)piperidin-1- yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 363 27

3-methyl-2-(4-((1- methyl-1H-indo1-5- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 377    28A   28B

(R)-3-((1-(3,6,7- trimethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile and (S)-3-((1-(3,6,7-trimethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 377 377    29A   29B

2-((3S,4R)-4-((6- methoxypyridin-3- yl)oxy)-3- methylpiperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one and2-((3R,4S)-4-((6- methoxypyridin-3- yl)oxy)-3- methylpiperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 369 369 30

2-((3R,4R)-3- fluoro-4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 373 31

2-((3S,4R)-3- fluoro-4-((1- methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-3,6-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 410 32

3,6-dimethyl-2-(4- ((1-methyl-1H- indazol-5- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 392 33

2-((3S,4R)-3- fluoro-4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3,6-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 387 34

2-(4-((6- ethoxypyridin-3- yl)oxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 369 35

2-((3S,4R)-3- fluoro-4- phenoxypiperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 342 36

1-(((1-(3-methyl-5- oxo-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)methyl)cyclo- propane-1- carbonitrile 327 37

2-(4-((6- cyclobutoxypyridin- 3-yl)oxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 395 38

2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-3,6-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 380 39

2-((3S,4R)-4-((1,3- dihydro-2- benzofuran-4- yl)oxy)-3-fluoropiperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 384 40

2-((3S,4R)-4-((1,3- dihydro-2- benzofuran-5- yl)oxy)-3-fluoropiperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 384 41

3-methyl-2-(4- ((tetrahydrofuran-3- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 318 42

3-methyl-2-(4- ((tetrahydro-2H- pyran-4- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 332    43A   43B

3-(((3R,4R)-3- hydroxy-1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2- yl)piperidin-4- yl)oxy)benzonitrile and 3-(((3S,4S)-3-hydroxy-1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 365 365 44

2-(4-((2,3-dihydro- 1H-inden-5- yl)oxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 364 45

3-(((3S,4R)-1-(3,6- dimethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)-3- fluoropiperidin-4- yl)oxy)benzonitrile 381 46

2-((3S,4R)-4-((1,3- dihydro-2- benzofuran-5- yl)oxy)-3-fluoropiperidin-1- yl)-3,6-dimethyl- 6,7-dihydro-SH- pyrrolo[3,4-b]pyridin-5-one 398 47

2-(4-(4- methoxyphenoxy) piperidin-1-yl)-3- methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 354    47A

3-methyl-2-(4-(3- (methylsulfonyl) phenoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 402 48

2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 367    48A

2-((3R,4R)-4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)-3-fluoropiperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 385 49

2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-3,6-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 381 50

5-((1-(3-methyl-5- oxo-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-2-yl)piperidin-4- yl)oxy)nicotinonitrile 350 51

2-(4-(3- methoxyphenoxy) piperidin-1-yl)-3- methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 354 52

2-(4-((7,8-dihydro- 5H-pyrano[4,3- b]pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 381 53

2-(4-((7,8-dihydro- 5H-pyrano[4,3- b]pyridin-3- yl)oxy)piperidin-1-yl)-3,6-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 395 54

2-(4-(2- ethoxyethoxy)piper- idin-1-yl)-3- methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 320 55

2-(4- ethoxypiperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 276 56

2-(4-(2- methoxyethoxy) piperidin-1-yl)-3- methyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 306 57

2-(4-(3- (methoxymethyl) phenoxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 368 58

2-(4-(3-((2- methoxyethoxy)meth- yl)phenoxy)piperi- din-1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 412 59

2-(4-((6,7-dihydro- 5H- cyclopenta[b]pyridin- 3- yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 365 60

2-((3R,4R)-3- fluoro-4-((6-(2- methoxyethoxy) pyridin-3-yl)oxy)piperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 417 61

2-((3R,4S)-3- fluoro-4-((6-(2- methoxyethoxy) pyridin-3-yl)oxy)piperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 417 62

2-(4-((6- isopropoxypyridin- 3-yl)oxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 383 63

2-(4- (benzyloxy)piperidin- 1-yl)-3-methyl- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 338 64

2-(4-((2,2-difluoro- 1- methylcyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 352    64A

2-(4-((1- fluorocyclopropyl) methoxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 320 65

2-((3S,4R)-4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)-3-fluoropiperidin-1- yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 385    65A

3-methyl-2-(4-(2- (1- methylcyclopropyl) ethoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4- b]pyridin-5-one 330

Example 66

3-Methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 2)

To a solution of2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(30 mg, 0.121 mmol, intermediate H1), 5-methylpyridin-3-ol (13.24 mg,0.121 mmol) and triphenylphosphine (47.7 mg, 0.182 mmol) in toluene (1mL) was added (E)-di-tert-butyl diazene-1,2-dicarboxylate (41.9 mg,0.182 mmol). The reaction mixture was stirred at 100° C. for 16 h. Thesolvent was evaporated under reduced pressure and was direcly purifiedby reverse phase HPLC (ACN/water with 0.1% TFA modifier) to yield thetitle compound. MS: 339 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 8.49(1H, s), 8.32 (1H, s), 8.17 (1H, s), 7.82 (1H, s), 4.91-4.92 (1H, m),4.34 (2H, s), 3.59-3.63 (2H, m), 3.25-3.29 (2H, m), 2.56 (3H, s), 2.40(3H, s), 2.22-2.26 (2H, m), 1.97-2.06 (2H, m).

The following examples in table 2 were prepared according to scheme 2using the procedure outlined in the synthesis of Example 66 using aknown or prepared phenol. Alternative conditions includes the use of THFas solvent and reaction temperatures that range from 50-100° C. asdictated by each substrate.

TABLE 2 Example Structure Name MS (M + 1)  67

3-methyl-2-(4-((2- methyl-3- oxoisoindolin-5- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 393  68

3-methyl-2-(4-(pyridin- 3-yloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 325  69

3-methyl-2-(4-((2- methylbenzo[d]oxazol- 6-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 379  70

2-(4-((1H-pyrrolo[2,3- b]pyridin-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 364  71

2-(4-(3- fluorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 342  72

2-(4-(4- fluorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 342  73

2-(4-(2- chlorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 358  74

2-(4-(3- chlorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 358  75

2-(4-(2- fluorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 342  76

2-(4-(4- chlorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 358  77

3-methyl-2-(4-(pyridin- 4-yloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 325  78

3-methyl-2-(4-(m- tolyloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 338  79

3-methyl-2-(4-(o- tolyloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 338  80

2-(4-(benzo[d]oxazol- 5-yloxy)piperidin-1- yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 365  81

2-(4-(3,4- difluorophenoxy)piperidin- 1-yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 360  82

2-(4-(3-chloro-4- methylphenoxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 372  83

3-methyl-2-(4-(p- tolyloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 338  84

4-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 349  85

5-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)picolinonitrile 350  86

2-(4-(isoxazol-3- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 315  87

methyl 5-((1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)picolinate 383  88

3-methyl-2-(4-((6- (trifluoromethyl)pyridin- 3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 393  89

2-(4-(benzo[d]oxazol- 6-yloxy)piperidin-1- yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 365  90

2-(4-((2- methoxypyridin-4- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 355  91

2-(4-((6-fluoropyridin- 3-yl)oxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 343  92

3-methyl-2-(4- (quinolin-7- yloxy)piperidin-1-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 375  93

4-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)picolinonitrile 350  93A

3-((1-(3-ethyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 363  94

2-(4-((2- methoxypyrimidin-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 356  94A

3-((1-(3,4-dimethyl-5- oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 363  95

3-((endo-8-(3-methyl- 5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)-8- azabicyclo[3.2.1]octan- 3-yl)oxy)benzonitrile 375  96

3-((exo-8-(3-methyl-5- oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)-8-azabicyclo [3.2.1]octan-3-yl) oxy)benzonitrile 375  97

2-(endo-3-((6- methoxypyridin-3- yl)oxy)-8- azabicyclo[3.2.1]octan-8-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 381 98

3-methyl-2-(exo-3-((1- methyl-1H-indazol-5- yl)oxy)-8-azabicyclo[3.2.1]octan- 8-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 404 99

2-(exo-3-((6- methoxypyridin-3- yl)oxy)-8- azabicyclo[3.2.1]octan-8-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 381 100

3-methyl-2-(endo-3- ((1-methyl-1H- indazol-5-yl)oxy)-8-azabicyclo[3.2.1]octan- 8-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 404 101

2-(4-((5- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 355 102

3-methyl-2-(4-((2- (trifluoromethoxy) pyridin-4-yl)oxy)piperidin-1-yl)-6,7- dihydro-5H-pyrrolo [3,4-b]pyridin-5- one 409 103

2-(4-((5-fluoropyridin- 3-yl)oxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 343 104

2-(4-((6-aminopyridin- 3-yl)oxy)piperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 340 105

2-(4-((6-(azetidin-1- yl)pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 380 106¹

2-(4-((6- (dimethylamino)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 368 107

2-(4-((3,4-dihydro-2H- benzo[b][1,4]oxazin-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 381 108

2-(4-(4-fluoro-3- methylphenoxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 356 109

2-(4-((2,3- dihydrobenzofuran-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 366 110²

3-methyl-2-(4-((3-oxo- 1,3-dihydro-2- benzofuran-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 380111

methyl 5-((1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)nicotinate 383 112

2-(4-(isochroman-7- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 380 113³

2-(4-(chroman-7- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 380 114

2-(4-((5,6- dimethylpyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 353 115

2-(4-((6-methoxy-5- methylpyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 369 116

2-(4-(chroman-6- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 380 117

3-methyl-2-(4-((3- methyl-1H-indazol-5- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 378 118

6-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)-3,4- dihydroquinolin-2(1H)- one 393 119

2-(4-(3,4- dimethylphenoxy) piperidin-1-yl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4-b] pyridin-5-one 352 120

3-methyl-2-(4-((6- (2,2,2- trifluoroethoxy)pyridin-3-yl)oxy)piperidin-1- yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one423 121⁴

3-methyl-2-(4-((1- oxoisochroman-6- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 394 122

3-methyl-2-(4-((2- methylbenzo[d]thiazol- 6-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 395 123

3-methyl-2-(4-((2- methylbenzo[d]oxazol- 5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 379 124

3-methyl-2-(4-((6- (trifluoromethoxy) pyridin-3-yl)oxy)piperidin-1-yl)-6,7- dihydro-5H-pyrrolo [3,4-b]pyridin-5- one 409 125

2-(4-((4,4- dimethylchroman-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 408 126⁵

2-(4-((1,1-dimethyl- 1,3-dihydro-2- benzofuran-5-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 394 127⁶

2-(4-((2,2- dimethylchroman-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 408 128

7-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)quinolin-2(1H)- one 391 129

2-(4-((1,3-dimethyl- 1H-indazol-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 392 130⁷

2-(4-((3,3-dimethyl- 2,3-dihydrobenzofuran- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 394 131

3-methyl-2-(4-(pyridin- 2-yloxy)piperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 325 132

2-(4-((2,3- dihydrobenzo[b][1,4] dioxin-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 382 133

7-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)-2H- benzo[b][1,4]oxazin- 3(4H)-one 395 134

2-(4-(3-fluoro-4- methylphenoxy) piperidin-1-yl)- 3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 356 135

7-((1-(3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)-3,4- dihydroisoquinolin- 1(2H)-one 393 136

3-methyl-6-((1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)oxazolo[4,5- b]pyridin-2(3H)-one 396 137

tert-butyl 7-((1-(3- methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)-3,4-dihydroisoquinoline- 2(1H)-carboxylate 479 138⁸

2-methyl-7-((1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)-3,4- dihydroisoquinolin- 1(2H)-one 407 139

3-methyl-2-(4-((1- methyl-1H-pyrazol-4- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 328 139A⁹

3-methyl-2-(4-((3-oxo- 2,3-dihydrobenzofuran- 5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 380 140

2-(4-(imidazo[1,2- a]pyridin-7- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 314 ¹Phenol may beprepared according to literature procedures, see e.g.: Chekler, E. L.;et al. J. Med. Chem. 2014, 57, 2462-2471. ²Phenol may be preparedaccording to literature procedures, see e.g.: Teixeira; et al. J. Mol.Struct. 2014, 1061, 61-68. 3Phenol may be prepared according toliterature procedures, see e.g.: Cube, R. V.; et al. Bioorg. Med. Chem.Letters 2005, 9, 2389-2393. ⁴Phenol may be prepared according toliterature procedures, see e.g.: Schwink, L., et al., PCT Patent Publ'nWO2009/021740. ⁵Phenol may be prepared according to literatureprocedures, see e.g.: Wu, et al., J. Org. Chem. 1998, 63, 5064-5070.⁶Phenol may be prepared according to literature procedures, see e.g.:Naik, et al., Tetrahedron 2014, 34, 5221-5233. ⁷Phenol may be preparedaccording to literature procedures, see e.g.: Alvaro, G., et al., PCTPatent Publ'n WO2012/168710. ⁸Phenol may be prepared according toliterature procedures, see e.g.: Yamashita, H., et al. PCT Patent Publ'nWO2006/112464. ⁹Phenol may be prepared according to literatureprocedures, see e.g.: Haudecoeur, R., et. al. J. Med. Chem. 2011, 54,5395-5402.

Example 141A and 141B

(R)-2-(4-((6-((1-Hydroxypropan-2-yl)oxy)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(4-((6-((1-hydroxypropan-2-yl)oxy)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 3) Step 1:2-(4-((6-(2-((tert-Butyldiphenylsilyl)oxy)propoxy)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of 2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one (170mg, 0.687 mmol, intermediate H1) in toluene (10 mL) was added6-(2-((tert-butyldiphenylsilyl)oxy)propoxy)pyridin-3-ol (280 mg, 0.343mmol), triphenylphosphine (270 mg, 1.03 mmol) and (E)-di-tert-butyldiazene-1,2-dicarboxylate (237 mg, 1.03 mmol). This mixture was stirredat 70° C. under a nitrogen atmosphere for 40 h. Volatiles were removedunder reduced pressure and the reaction was concentrated. The residuewas purified by silica gel chromatography (0-75% EtOAc/petroleum ether)to yield the title compound. MS: 637 (M+1)

Step 2:2-(4-((6-((1-Hydroxypropan-2-yl)oxy)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-(2-((tert-butyldiphenylsilyl)oxy)propoxy)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(220 mg, 0.130 mmol) in THF (5 mL) was added TBAF (0.259 mL, 0.259mmol). The mixture was stirred at 60° C. under a nitrogen atmosphere for15 h. The reaction was cooled and treated with water (5 mL) andextracted with EtOAc (15 mL×3). The combined organic layers were driedover anhydrous Na₂SO₄, filtered and concentrated. The residue waspurified by reverse phase HPLC (ACN/water with 0.1% NH₃OH modifier) toafford the title compound. The mixture of the two stereoisomers waspurified by chiral SFC (AD column, 40% ethanol with 0.05% DEAmodifier/CO₂) to afford isomer 141A (faster eluting): MS: 399 (M+1). ¹HNMR (400 MHz, CDCl₃): 7.79 (2H, s), 7.24-7.28 (1H, overlapped), 6.72(1H, d, J=9.2 Hz), 5.99 (1H, s), 5.02-5.04 (1H, m), 4.33-4.38 (3H, m),3.98-4.00 (1H, m), 3.72-3.76 (2H, m), 3.52-3.56 (2H, m), 3.10-3.15 (2H,m), 2.34 (3H, s), 2.07-2.09 (2H, m), 1.91-1.95 (2H, m), 1.31 (3H, d,J=6.8 Hz). Isomer 141B (slower eluting): MS: 399 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 7.79 (2H, s), 7.24-7.28 (1H, overlapped), 6.72 (1H, d, J=9.2Hz), 6.07 (1H, s), 5.02-5.04 (1H, m), 4.33-4.38 (3H, m), 3.98-4.00 (1H,m), 3.72-3.76 (2H, m), 3.52-3.56 (2H, m), 3.10-3.15 (2H, m), 2.34 (3H,s), 2.07-2.09 (2H, m), 1.91-1.95 (2H, m), 1.31 (3H, d, J=6.8 Hz).

The following examples in table 3A were prepared according to scheme 3using the procedure outlined in the synthesis of Example 141A and 141Busing known or prepared intermediates and phenols containingsilicon-based protecting groups such as TMS, SEM, TES, etc. Alternativeconditions for step 2 include temperature variation from RT-60° C. asdependent on the substrate.

TABLE 3A Example Structure Name MS (M + 1) 142*

2-(4-((1H-pyrazol-4- yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 314 143A 143B

(S)-2-(4-((6-((1- hydroxypropan-2- yl)oxy)pyridin-3-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one and (R)-2-(4-((6-((1- hydroxypropan-2- yl)oxy)pyridin-3-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 399 399 *Phenol may be prepared according to literatureprocedures, see e.g.: Oslob, et al., PCT Patent Publ'n WO2014/008197.

Example 144

3-Methyl-2-(4-((1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 3) Step 1: tert-Butyl6-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate

To a solution of tert-butyl6-hydroxy-3,4-dihydroisoquinoline-2(1H)-carboxylate (200 mg, 0.802 mmol)in toluene (15 mL) was added2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(218 mg, 0.882 mmol, intermediate H1), triphenylphosphine (379 mg, 1.444mmol) and (E)-tert-butyl 2-pivaloyldiazenecarboxylate (309 mg, 1.444mmol), the resulting mixture was stirred at 80° C. under a nitrogenatmosphere for 15 h. The mixture was filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (10/1 petroleum ether/EtOAc) to afford the titlecompound. MS: 479 (M+1).

Step 2:3-Methyl-2-(4-((1,2,3,4-tetrahydroisoquinolin-6-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of tert-butyl6-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)-3,4-dihydroisoquinoline-2(1H)-carboxylate(170 mg, 0.355 mmol) in MeOH (2 mL) was added HCl (1.0 mL, 12.18 mmol, 4M in dioxane). The mixture was stirred at RT for 3 h under a ntirogenatmosphere. The mixture was concentrated and diluted with EtOAc (30 mL)and water (10 mL). The organic layer was washed with water (10 mL×2),brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by reverse phase HPLC(ACN/water with 0.1% NH₃OH modifier) to afford the title compound. MS:379 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.82 (1H, s), 6.96 (1H, d, J=8.0Hz), 6.77 (1H, dd, J=8.0, 2.8 Hz), 6.71 (1H, s), 5.95 (1H, s), 4.50-4.53(1H, m), 4.37 (2H, s), 3.99 (2H, s), 3.56-3.58 (2H, m), 3.13-3.22 (4H,m), 2.78-2.81 (2H, m), 2.37 (3H, s), 2.12-2.14 (2H, m), 1.96-1.99 (2H,m).

The following examples in table 3B were prepared according to scheme 3using the procedure outlined in the synthesis of Example 144 using knownor prepared intermediates and phenols containing a protecting groupsuseptible to acid-mediated cleavage using HCl or TFA.

TABLE 3B Example Structure Name MS (M + 1) 145

2-(4-((2,3-dihydro-1H- pyrido[2,3- b][1,4]oxazin-7-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 382 146

3-methyl-2-(4- ((1,2,3,4- tetrahydroisoquinolin- 7-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 379 147

2-(4-(isoindolin-5- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 365 148*

2-(4-((3,4-dihydro-2H- benzo[b][1,4]oxazin-7- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 381 149

3-methyl-2-(4-((2- methyl-1H- benzo[d]imidazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 378*Phenol may be prepared according to literature procedures, see e.g.:Yoshino, T., et al., Japan Patent Publication JP 2009/114140.

Example 150A and 150B

(R)-2-(4-(4-(1-Hydroxyethyl)phenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(4-(4-(1-hydroxyethyl)phenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 4) Step 1:2-(4-(4-Acetylphenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of 1-(4-hydroxyphenyl)ethanone (91 mg, 0.667 mmol),2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(150 mg, 0.607 mmol, intermediate H1), Ph₃P (239 mg, 0.910 mmol), DBAD(210 mg, 0.910 mmol) in toluene (4 mL) was stirred at 80° C. for 16 hunder nitrogen. The reaction was concentrated to give a residue whichwas purified by prep-TLC (100% EtOAc) to give title compound. MS: 366(M+1).

Step 2:2-(4-(4-(1-Hydroxyethyl)phenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of2-(4-(4-acetylphenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(130 mg, 0.356 mmol) in THF (2 mL) was added LiBH₄ (15.50 mg, 0.711mmol) and was stirred at 20° C. for 16 h. The reaction mixture wasconcentrated to give a residue which was used purified by silica gelchromatography (20/1 DCM/MeOH) to afford the title compound. The mixtureof the two stereoisomers was purified by chiral SFC (OJ column, 5-40%MeOH with 0.05% DEA modifier/CO₂) to afford isomer 150A (fastereluting): MS: 368 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.78 (1H, s),7.27 (2H, J=8.80 Hz, d), 6.93 (2H, J=8.80 Hz, d), 4.72-4.77 (1H, m),4.54-4.62 (1H, m), 4.32 (2H, s), 3.49-3.60 (2H, m), 3.13-3.25 (2H, m),2.37 (3H, s), 2.07-2.20 (2H, m), 1.82-1.95 (2H, m), 1.40 (3H, J=6.80 Hz,d). Isomer 150B (slower eluting): MS: 368 (M+1). ¹H NMR (400 MHz,methanol-d₄): δ 7.78 (1H, s), 7.27 (2H, J=8.80 Hz, d), 6.93 (2H, J=8.80Hz, d), 4.71-4.79 (1H, m), 4.53-4.62 (1H, m), 4.31 (2H, s), 3.49-3.61(2H, m), 3.13-3.25 (2H, m), 2.36 (3H, s), 2.05-2.18 (2H, m), 1.82-1.96(2H, m), 1.40 (3H, J=6.40 Hz, d).

The following examples in table 4 were prepared according to scheme 4using the procedure outlined in the synthesis of Examples 150A and 150Bwhere step 1 includes phenols with ketone or ester substiuents.Alternative reaction conditions for step 2 may utilize sodiumborohydride as the reagent as appropriate for the substrate.

TABLE 4 Example Structure Name MS (M + 1) 151

2-(4-(4- (hydroxymethyl) phenoxy)piperidin-1-yl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 354 152

2-(4-((2- (hydroxymethyl)pyridin- 4-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 355 153

2-(4-((1-(2- hydroxyethyl)-3- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 422 154

(S)-2-(4-((3-(2- hydroxyethyl)-2,3- dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 155

2-(4-((6- (hydroxymethyl)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 355 156

2-(4-((5- (hydroxymethyl)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 355 157A*157B*

(R)-2-(4-((1-(2- hydroxyethyl)-2,3- dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one and (S)-2-(4-((1-(2- hydroxyethyl)-2,3-dihydro-1H-inden-5- yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 408 408 *Phenol may be preparedaccording to literature procedures, see e.g.: Colandrea, et al. PCTPatent Publication WO2005/058848.

Examples 158A and 158B

cis-2-(3,3-Difluoro-4-phenoxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneandtrans-2-(3,3-Difluoro-4-phenoxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 5) Step 1: Methyl2-cyano-6-(3,3-difluoro-4-phenoxypiperidin-1-yl)-5-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (230 mg,1.09 mmol) in NMP (5 mL) was added 3,3-difluoro-4-phenoxypiperidine (233mg, 1.09 mmol) and triethylamine (0.304 mL, 2.18 mmol). The mixture wasstirred at 120° C. for 16 h under a nitrogen atmosphere (balloon). Thereaction was concentrated in vacuo and the resultant residue waspurified by silica gel chromatography (10:1-1:4 petroleum ether:EtOAc)to give the title compound. MS: 388 (M+1).

Step 2:2-(3,3-Difluoro-4-phenoxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-6-(3,3-difluoro-4-phenoxypiperidin-1-yl)-5-methylnicotinate (240mg, 0.62 mmol) in MeOH (2 mL) and ammonium hydroxide (0.5 mL, 0.622mmol) was added nickel (72.7 mg, 1.24 mmol). The system was placed underhydrogen (50 psi) and was heated to 30° C. for 3 h. After filtration,washing with methanol, the filtrate was concentrated under reducedpressure. The residue was purified by reverse phase HPLC (ACN/water with0.1% NH₃OH modifier) to afford the title compound. The mixture of thetwo stereoisomers was purified by chiral SFC (OD column, 30% isopropanolwith 0.05% DEA modifier/CO₂) to afford isomer 158A (faster eluting): MS:360 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (1H, s), 7.24 (2H, t, J=8.0Hz), 7.07 (1H, br s), 6.93-6.97 (3H, m), 4.54-4.55 (1H, m), 4.31 (2H,s), 3.76-3.86 (1H, m), 3.66-3.68 (1H, m), 3.29-3.34 (2H, m), 2.32 (3H,s), 2.12-2.22 (2H, m). Isomer 158B (slower eluting): MS: 360 (M+1). ¹HNMR (400 MHz, CDCl₃): δ 7.78 (1H, s), 7.25 (2H, t, J=8.0 Hz), 6.94-6.98(3H, m), 6.61 (1H, br s), 4.55-4.56 (1H, m), 4.31 (2H, s), 3.66-3.72(1H, m), 3.55-3.58 (1H, m), 3.29-3.34 (2H, m), 2.32 (3H, s), 2.14-2.22(2H, m).

Example 159

2-[4-(1,3-Dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 5) Step 1: Methyl2-cyano-6-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-5-methylnicotinate

To a solution of 4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidine (4.19g, 18.4 mmol) and methyl 6-chloro-2-cyano-5-methylnicotinate (3.86 g,18.4 mmol) in NMP (42 mL) was added N,N-diisopropylethylamine (9.8 mL,55 mmol) under an atmosphere of nitrogen. The resulting mixture washeated to 60° C. with stirring for 15 h. After cooling to RT, methanol(42 mL) and water (42 mL) were added to the reaction mixture. The solidswere isolated by filtration to yield the title compound. MS: 394 (M+1).

Step 2:2-[4-(1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-6-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-5-methylnicotinate(14.6 g, 14.8 mmol) in 2,2,2-trifluoroethanol (175 mL) was added spongeNi/Mo catalyst (2.92 g) under a nitrogen atmosphere. The system wasplaced under hydrogen (50 psi) and was heated to 30° C. for 24 h. Afterfiltration, washing with 2,2,2-trifluoroethanol (40 mL×4), the volatileswere removed under reduced pressure. The residue was diluted with THF(60 mL) and was heated to 60° C. The solution was evaporated toapproximately half the original volume before IPAc (60 mL) was added at50° C. The mixture further evaporated and cooled to RT before the titlecompound was isolated by filtration. MS: 366 (M+1). ¹H NMR (DMSO-d₆): δ8.33 (1H, s), 7.72 (1H, s), 7.20 (1H, d, J=8.23 Hz), 6.96 (1H, s), 6.90(1H, d, J=8.33 Hz), 4.94 (4H, d, J=13.22 Hz), 4.56-4.59 (1H, m), 4.24(2H, s), 3.48 (2H, d, J=12.74 Hz), 3.10 (2H, t, J=10.78 Hz), 2.31 (3H,s), 2.07 (2H, br s), 1.74-1.80 (2H, m).

Example 160

Methyl2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate(Scheme 5) Step 1: Dimethyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridine-3,5-dicarboxylate

N,N-Diisopropylethylamine (0.634 mL, 3.63 mmol) was added to a stirredmixture of 2-methoxy-5-(piperidin-4-yloxy)pyridine dihydrochloride (409mg, 1.45 mmol, intermediate F1) and dimethyl2-chloro-6-cyanopyridine-3,5-dicarboxylate (185 mg, 0.727 mmol,intermediate A4) in dioxane (10 mL). The reaction was stirred at 100° C.for 1 h and was then concentrated. The residue was purified by columnchromatography on silica gel (1/3 EtOAc/hexane) to give the titlecompound. MS: 427 (M+1).

Step 2:2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Platinum(IV) oxide (1.12 mg, 4.92 μmol) was added to a stirred, roomtemperature mixture of dimethyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)pyridine-3,5-dicarboxylate(21 mg, 0.049 mmol) in MeOH (10.0 mL). The reaction was stirred at RTunder an atmosphere of hydrogen for 3 h. After filtration and removal ofsolvent, the crude residue was transferred to a microwave vial withdioxane (10 mL), to which triethylamine (68 μL, 0.49 mmol) was added.The resulting mixture was stirred at 100° C. under microwaveirradiation. After concentrating the reaction, the residue was purifiedby mass triggered reverse phase HPLC (ACN/water with 0.1% NH₃OHmodifier) to afford the title compound. MS: 399 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 8.39 (1H, s), 7.88 (1H, d, J=3.0 Hz), 7.29 (1H, dd, J=8.9,3.0), 7.02 (1H, s), 6.72 (1H, d, J=8.9 Hz), 4.47 (1H, t, J=5.8 Hz), 4.38(2H, s), 3.92 (6H, s), 3.79-3.83 (2H, m), 3.46-3.51 (2H, m), 2.06-2.10(2H, m), 1.90-1.93 (2H, m).

Example 160A and 160B

2-(4-(((1S,2S)-2-Fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand2-(4-(((1R,2R)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 5) Step 1: Methyl2-cyano-6-(4-(((trans)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinateand methyl2-cyano-6-(4-(((cis)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinate

A solution of 4-((2-fluoro-1-methylcyclopropyl)methoxy)piperidine(intermediate KK, 200 mg) in DMF (5 mL) was added methyl6-chloro-2-cyano-5-methylnicotinate (intermediate A1, 225 mg, 1.068mmol) and DIPEA (414 mg, 3.20 mmol) was stirred at 80° C. for 15 h. Themixture was directly purified by reverse phase HPLC (ACN/water with 0.1%TFA modifier) to afford the title compounds, the trans-isomer elutedfirst and the cis-isomer eluted second. MS: 362 (M+1).

Step 2:2-(4-(((1S,2S)-2-Fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand2-(4-(((1R,2R)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of methyl2-cyano-6-(4-(((trans)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinatein MeOH (5 mL) was added nickel (30 mg, 0.511 mmol) and 2 drops ofconcentrated ammonia was stirred at RT for 3 h under a hydrogenatmosphere (50 psi). The mixture was filtered and concentrated beforethe two stereoisomers were purified by chiral SFC (OJ column, 15%ethanol/CO₂) to afford isomer 160A (faster eluting isomer): MS: 334(M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (1H, s), 6.03 (1H, s), 4.32-4.50(3H, m), 3.67 (1H, dd, J=10.0 Hz, 2.4 Hz), 3.48-3.57 (4H, m), 2.99-3.05(2H, m), 2.33 (3H, s), 2.01-2.05 (2H, m), 1.73-1.78 (2H, m), 1.09 (3H,d, J=3.2 Hz), 0.81-0.86 (1H, m), 0.62-0.66 (1H, m). Isomer 160B (slowereluting isomer): MS: 334 (M+1). ¹H NMR (400 MHz, CDCl₃) δ 7.77 (1H, s),6.03 (1H, s), 4.32-4.50 (3H, m), 3.67 (1H, dd, J=10.0 Hz, 2.4 Hz),3.48-3.57 (4H, m), 2.99-3.05 (2H, m), 2.33 (3H, s), 2.01-2.05 (2H, m),1.73-1.78 (2H, m), 1.09 (3H, d, J=3.2 Hz), 0.81-0.86 (1H, m), 0.62-0.66(1H, m).

Example 160C and 160D

2-(4-(((1S,2R)-2-Fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand2-(4-(((1R,2S)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 5)

Methyl2-cyano-6-(4-(((cis)-2-fluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinatefrom step 1 in procedure for Example 160A and 160B (vide supra) (100 mg,0.277 mmol) was dissolved in MeOH (5 mL). Nickel (30 mg, 0.511 mmol) and2 drops of concentrated ammonia was added to the solution and thereaction was stirred at RT for 3 h under an atmosphere of hydrogen (50psi). The mixture was filtered and concentrated before resolution bychiral SFC (OJ column, 15% EtOH with 0.1% ammonium hydroxide/CO₂) toafford isomer 160C (faster eluting isomer): MS: 334 (M+1). ¹H NMR (400MHz, CDCl₃): δ 7.77 (1H, s), 6.10 (1H, s), 4.38-4.57 (1H, m), 4.34 (2H,s), 3.47-3.52 (3H, m), 3.33 (1H, dd, J=9.2 Hz, 2.8 Hz), 3.23 (1H, d,J=9.2 Hz), 2.99-3.06 (2H, m), 2.32 (3H, s), 1.95-1.99 (2H, m), 1.57-1.73(2H, m), 1.09 (3H, d, J=1.6 Hz), 0.73-0.80 (1H, m), 0.63-0.70 (1H, m).Isomer 160D (slower eluting isomer): MS: 334 (M+1). ¹H NMR (400 MHz,CDCl₃): δ 7.77 (1H, s), 6.10 (1H, s), 4.38-4.57 (1H, m), 4.34 (2H, s),3.47-3.52 (3H, m), 3.33 (1H, dd, J=9.2 Hz, 2.8 Hz), 3.23 (1H, d, J=9.2Hz), 2.99-3.06 (2H, m), 2.32 (3H, s), 1.95-1.99 (2H, m), 1.57-1.73 (2H,m), 1.09 (3H, d, J=1.6 Hz), 0.73-0.80 (1H, m), 0.63-0.70 (1H, m).

Example 161

3-Methyl-2-(4-(pyridin-3-ylmethoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneStep 1: Methyl2-cyano-5-methyl-6-(4-(pyridin-3-ylmethoxy)piperidin-1-yl)nicotinate

To a solution of 3-((piperidin-4-yloxy)methyl)pyridine hydrochloride (80mg, 0.350 mmol) in DMF (5 mL) was added TEA (0.69 mL, 4.94 mmol). Themixture was stirred 16 h at 80° C. The mixture was cooled to RT, dilutedwith brine (10 mL) and extracted with EtOAc (20 mL×4). The combinedorganic layers were washed with brine (5 mL), dried over anhydroussodium sulfate, filtered and concentrated. The residue was purified bysilica gel chromatography (30-80% EtOAc in petroleum ether) to give thetitle compound. MS: 367 (M+1).

Step 2:3-Methyl-2-(4-(pyridin-3-ylmethoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-5-methyl-6-(4-(pyridin-3-ylmethoxy)piperidin-1-yl)nicotinate (60mg, 0.164 mmol) in MeOH (10 mL) was added cobalt(II) chloride (63.8 mg,0.491 mmol). The mixture was stirred 5 min at RT and NaBH₄ (18.59 mg,0.491 mmol) was added portionwise. The reaction mixture was stirred 1 hat 15° C. before the volatiles were removed under reduced pressure. Theresidue was diluted with EtOH (20 mL) and DIEA (0.405 mL, 2.32 mmol) andwas stirred 2 h at 50° C. The mixture was filtered through a pad ofsilica gel and the filtrate was concentrated. Purification by reversephase HPLC (ACN/water with ammonium hydroxide modifier) afforded thetitle compound. MS: 339 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 8.61 (1H, s),8.53 (1H, d, J=4.4 Hz), 7.78 (1H, s), 7.72 (1H, d, J=7.6 Hz), 7.25-7.32(1H, m), 6.04 (1H, s), 4.62 (2H, s), 4.34 (2H, s), 3.58 (1H, br s),3.54-3.55 (2H, m), 3.04 (2H, t, J=6.0 Hz), 2.34 (3H, s), 2.07 (2H, m),1.80-1.86 (2H, m).

Example 161A

2-((3S,4R)-3-Fluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneStep 1: Methyl2-cyano-6-((3S,4R)-3-fluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-4,5-dimethylnicotinate

(3S,4R)-3-fluoro-4-((1-methylcyclopropyl)methoxy)piperidine(intermediate L1A, 492 mg, 2.63 mmol) and methyl6-chloro-2-cyano-4,5-dimethylnicotinate (intermediate AB, 393 mg, 1.75mmol) were dissolved in NMP (7.5 mL) and DIPEA (0.611 mL, 3.50 mmol).The reaction was heated to 65° C. for 39 h and was cooled to RT. Themixture was partitioned between aqueous NH₄Cl and EtOAc. The organiclayer was washed with water, then brine, dried over anhydrous sodiumsulfate, filtered and concentrated. The residue was purified by silicagel chromatography (60% DCM/hexanes) to give the title compound. MS: 376(M+1).

Step 2:2-((3S,4R)-3-Fluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Methyl2-cyano-6-((3S,4R)-3-fluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-4,5-dimethylnicotinate(0.395 g, 1.05 mmol) was dissolved in EtOH (7.5 mL) and AcOH (0.30 mL,5.26 mmol). Palladium on carbon (10 wt %, 0.112 g, 0.105 mmol) was addedand the system was placed under a hydrogen atmosphere and stirred for 5h before the mixture was filtered (EtOH wash). The filtrate wasconcentrated (azeotrope with toluene) and was dissolved in methanol (6mL) and triethylamine (1.0 mL, 7.89 mmol) and stirred for 90 min at RT.The volatiles were removed under reduced pressure and the resultantresidue was purified by silica gel chromatography (0-50% 3:1 EtOAc:EtOHin DCM) to afford the title compound. MS: 348 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 6.03 (s, 1H), 4.93 (m, 0.5H), 4.83 (m, 0.5H), 4.28 (s, 2H),3.68 (m, 2H), 3.40 (m, 3H), 3.25 (m, 1H), 2.97 (m, 1H), 2.63 (s, 3H),2.25 (s, 3H), 2.14 (m, 1H), 1.88 (m, 1H), 1.17 (s, 3H), 0.44 (m, 2H),0.35 (m, 2H).

The following examples in table 5 were prepared according to scheme 5using the procedure and conditions outlined in the synthesis of Examples158A, 158B, 159, 160, 160A, 160B, 160C, 160D, 161 and 161A.

TABLE 5 Example Structure Name MS (M + 1) 162

2-((3S,4R)-3-fluoro-4- ((2- methylbenzo[d]oxazol- 6-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 397 162A 162B

(R)-2-(4-((2-methoxy- 2,3-dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one and(S)-2-(4-((2-methoxy- 2,3-dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 394 394 163

2-((3S,4R)-3-fluoro-4- ((2-methyl-3- oxoisoindolin-5-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 411 163A

2-(4-((1H- benzo[d][1,2,3]triazol- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 365 164

2-((3S,4R)-3-fluoro-4- ((6-methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 373 164A

2-((3S,4R)-4-((5,7- dihydrofuro[3,4- b]pyridin-3-yl)oxy)-3-fluoropiperidin-1-yl)-3- ethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 399 165

2-((3R,4S) or (3S,4R)- 3-fluoro-4-(pyridin-3- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 343 165A

2-((3S,4R)-4-((5,7- dihydrofuro[3,4- b]pyridin-3-yl)oxy)-3-fluoropiperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 399 166

2-((3S,4R) or (3R,4S)- 3-fluoro-4-(pyridin-3- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 343 166A 166B

(R)-3-ethyl-2-(4-((2- hydroxy-2,3-dihydro- 1H-inden-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one and(S)-3-ethyl-2-(4-((2- hydroxy-2,3-dihydro- 1H-inden-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 394394 167

2-(4-((1H-indazol-5- yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 364 167A

3-methyl-2-(4-((2- oxido-1,3- dihydrobenzo[c] thiophen-5-yl)oxy)piperidin- 1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one398 168

2-(4-((6-(2- (dimethylamino)ethoxy) pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 412 168A 168B

(R)-3-methyl-2-(4-((2- oxido-1,3- dihydrobenzo[c] thiophen-5-yl)oxy)piperidin- 1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-oneand (S)-3-methyl-2-(4-((2- oxido-1,3- dihydrobenzo[c] thiophen-5-yl)oxy)piperidin- 1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one398 398 169

2-(4-((6-(2-amino-2- methylpropoxy)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 412 169A

2-(4-((1-ethyl-1H- pyrazol-4- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 342 170

2-(4-((6-(2- hydroxyethoxy)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 385 170A

3-methyl-2-(4-((1- phenyl-1H-pyrazol-4- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 390 171

2-(4-((6-(2- methoxyethoxy)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 399 171A 171B

(R)-2-(3,3-difluoro-4- ((1- methylcyclopropyl) methoxy)piperidin-1-yl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-oneand (S)-2-(3,3-difluoro-4- ((1- methylcyclopropyl) methoxy)piperidin-1-yl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 352 352 172

2-(4- (cyclobutylmethoxy) piperidin-1-yl)-3- methyl- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 316 172A

3-methyl-2-(4-(2,2,2- trifluoroethoxy) piperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 330 173

2-(4-((6-(2-(azetidin-1- yl)ethoxy)pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 424 173A

3-ethyl-2-(4-((5- methylpyridin-3- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 353 174

N-(2-((5-((1-(3-methyl- 5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)pyridin-2- yl)oxy)ethyl)acetamide 426 174A

2-((3R,4R)-3-fluoro-4- ((1- methylcyclopropyl) methoxy) piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 348 175

2-(4- (cyclopentylmethoxy) piperidin-1-yl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 330 175A

3-methyl-2-(4-(pyridin- 4-ylmethoxy)piperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 339 176

3-methyl-2-(4-((1- methylcyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 316 176A

2-(4- (cyclopropylmethoxy) piperidin-1-yl)-3-ethyl- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 316 177

3-methyl-2-(4- ((tetrahydrofuran-3- yl)methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 332 178

3-methyl-2-(4-((1- methylcyclopentyl) methoxy)piperidin- 1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 344 178A

2-((3S,4R)-3-fluoro-4- (isochroman-6- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 398 178B

2-((3S,4R)-3-fluoro-4- (isochroman-7- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 398 179

3-methyl-2-(4-(3,3,3- trifluoro-2- hydroxypropoxy) piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 453 180

2-(4-((1- fluorocyclopentyl) methoxy)piperidin- 1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 348 181A 181B

(R)-3-methyl-2-(4- (3,3,3-trifluoro-2- hydroxypropoxy) piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one and(S)-3-methyl-2-(4- (3,3,3-trifluoro-2- hydroxypropoxy) piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 453 453 182

3-methyl-2-(4- (neopentyloxy) piperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 318 182A

2-(4-(imidazo[1,2- a]pyridin-6- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 364 183

3-methyl-2-(4-(oxazol- 2-ylmethoxy)piperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 329 184

3-methyl-2-(4-((1- methylcyclobutyl) methoxy)piperidin- 1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 330 185A 185B

2-((1R,5S)-6-((6- methoxypyridin-3- yl)oxy)-3- azabicyclo[3.1.1]heptan-3-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one and2-((1R,5S)-6-((6- methoxypyridin-3- yl)oxy)-3- azabicyclo[3.1.1]heptan-3-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 367 367 186

2-(4-((1- ethylcyclopropyl) methoxy) piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 330 187

2-(4- (bicyclo[1.1.1]pentan- 1-ylmethoxy)piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 328 187A

2-(4-((2,2-difluoro-1- methylcyclopropyl) methoxy)piperidin- 1-yl)-3-ethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 366 188

3-methyl-2-(4-(3,3,3- trifluoro-2- methylpropoxy) piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 358 189

3-methyl-2-(4-((1- (trifluoromethyl) cyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 370 190

methyl 2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridine- 4-carboxylate413 190A

3-methyl-2-(4-((1- methyl-1H-pyrazol-4- yl)methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 342 191

2-(4- (cyclohexylmethoxy) piperidin-1-yl)-3- methyl- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 344 191A 191B

(1S,2R)-2-methyl-2- (((1-(3-methyl-5-oxo- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)methyl) cyclopropane-1-carbonitrile and (1R,2S)-2-methyl-2- (((1-(3-methyl-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)methyl)cyclopropane- 1-carbonitrile 341 341 192

2-(4- isobutoxypiperidin-1- yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 304 193

2-(4-((1- methoxycyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 332 193A 193B

(1R,2R)-2-methyl-2- (((1-(3-methyl-5-oxo- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)methyl) cyclopropane-1-carbonitrile and (1S,2S)-2-methyl-2- (((1-(3-methyl-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)methyl)cyclopropane- 1-carbonitrile 341 341 194

2-(4-((3,4-dihydro-2H- pyrano[2,3-b]pyridin-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 381 194A

2-((3S,4R)-3-fluoro-4- (isochroman-7- yloxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 412 195

2-(4-(4- (methoxymethyl) phenoxy) piperidin-1-yl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 368 196

2-((3S,4R)-3-fluoro-4- (4- fluorophenoxy) piperidin- 1-yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 360 197

3-methyl-2-(4-((3- methyl-1H- pyrazolo[3,4-b]pyridin-5-yl)oxy)piperidin-1- yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one379 197A

2-(4- ([1,2,4]triazolo[1,5- a]pyridin-6- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 365 198

2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 366 198A

2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)-3-ethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 380 199A 199B

(R)-3-methyl-2-(4-((1- methyl-1,3-dihydro-2- benzofuran-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one and(S)-3-methyl-2-(4-((1- methyl-1,3-dihydro-2- benzofuran-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 380380 200

3-ethyl-2-(4- (isochroman-7- yloxy)piperidin-1-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 394 200A

3-ethyl-2-(4- (isochroman-6- yloxy)piperidin-1-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 394 201

3-ethyl-2-(4-(pyridin-3- yloxy)piperidin-1-yl)- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 339 201A

2-(4-((2,3- dihydrofuro[2,3- b]pyridin-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 367 202

3-ethyl-2-(4- phenoxypiperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 338 202A

3-methyl-2-(4-((2- methyl-2H-indazol-5- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 378 203

2-(4-((6- (methoxymethyl)pyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 369 204

2-(4-((6-((2- methoxyethoxy)methyl) pyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 413 205

2-(4-(4-((2- methoxyethoxy)methyl) phenoxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 412 205A

3-methyl-2-(4-(pyridin- 2-ylmethoxy)piperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 339 206

2-(4-((1H- pyrazolo[3,4-b]pyridin- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 365 206A

3-methyl-2-(4-((1- methyl-1H-pyrazol-4- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 342 207

2-(4-(isochroman-6- yloxy)piperidin-1-yl)- 3-methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 380 208

2-(4-((2,2- difluorobenzo[d][1,3] dioxol-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 404 208A

2-(4-((2,2-dioxido-1,3- dihydrobenzo[c] thiophen- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 414 209

2-(4-((1,2-dimethyl- 1H-benzo[d]imidazol- 5-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 392 210

2-(4-((1,2-dimethyl- 1H-benzo[d]imidazol- 6-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 392 211

methyl 2-(5-((1-(3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)-1H-indazol-1- yl)acetate 436 212

methyl 2-(4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridine-4-carboxylate 424 212A

2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-3-ethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 381 213

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-3-ethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 380 213A

2-((3R,4R)-4-((5,7- dihydrofuro[3,4- b]pyridin-3-yl)oxy)-3-fluoropiperidin-1-yl)-3- ethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 399 214

2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-3- ethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 398 215

3-ethyl-2-((3S,4R)- or (3R,4S)-3-fluoro-4- (pyridin-3-yloxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 357216

3-ethyl-2-((3R,4S)- or (3S,4R)-3-fluoro-4- (pyridin-3-yloxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 357216A

2-(4-((2,3- dihydrofuro[3,2- b]pyridin-6- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 367 217

2-((3R,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-3- ethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 398

Example 218

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 6) Step 1: Methyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-4-methylnicotinate (210 mg,0.997 mmol, intermediate I1) and DIPEA (0.52 mL, 2.99 mmol) in DMF (4mL) was added 2-methoxy-5-(piperidin-4-yloxy)pyridine (270 mg, 1.296mmol, intermediate F1). The reaction was stirred at 80° C. for 14 h. Themixture was diluted with water (10 mL) and extracted by EtOAc (10 mL×3).The combined organic phases were washed with water (15 mL×3), dried overanhydrous Na₂SO₄, filtered and concentrated to dryness. The residue waspurified by flash silica gel chromatography (0-25% EtOAc/petroleumether) to afford the title compound. MS: 383 (M+1).

Step 2:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methylnicotinate(295 mg, 0.771 mmol) in EtOH (10 mL) was added molybdenum-promotednickel (skeletal, 200 mg, 1.293 mmol). The mixture was degassed andplaced under hydrogen (50 psi) at 40° C. for 4 h. The reaction wasfiltered and the filtrate was concentrated under reduced pressure. Theresidue was purified by reverse phase HPLC (ACN/water with 0.1% TFAmodifier) to yield the title compound. MS: 355 (M+1)

Step 3:3-Bromo-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-ppyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(140 mg, 0.395 mmol) in CHCl₃ (3 mL) was added NBS (77 mg, 0.435 mmol).The reaction was stirred at 80° C. for 14 h and was then concentrated toform a residue. The crude material was purified by reverse phase HPLC(ACN/water with 0.1% TFA modifier) to yield the title compound. MS: 433,435 (M+1)

Step 4:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of3-bromo-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(40 mg, 0.092 mmol), trimethylboroxine (23.18 mg, 0.185 mmol) andtribasic potassium phosphate (39.2 mg, 0.185 mmol) was added[1,1′-bis(di-tert-butylphosphino)ferrocene]dichloropalladium(II) (6.02mg, 9.23 μmol). The mixture was degassed and backfilled with N₂(g) (3×)and stirred at 70° C. for 14 h. The solvent was removed in vacuo and thecrude residue was purified by reverse phase HPLC (ACN/water with 0.1%TFA modifier) to give the title compound. MS: 369 (M+1). ¹H NMR (400MHz, methanol-d₄) δ 7.88 (1H, d, J=2.4 Hz), 7.55 (1H, dd, J=3.2 Hz, 9.2Hz), 6.88 (1H, d, J=9.2 Hz), 4.53-4.54 (1H, m), 4.29 (2H, s), 3.90 (3H,s), 3.50-3.52 (2H, m), 3.15-3.20 (2H, m), 2.64 (3H, s), 2.29 (3H, s),2.12-2.16 (2H, m), 1.93-1.96 (2H, m).

The following examples in table 6 were prepared according to scheme 6using the procedure and conditions outlined in the synthesis of Example218 using prepared or known reactants in step 1 and appropriate boronicesters/acids or alkylzinc reagents in step 4. In some cases, the finalstep maybe omitted.

TABLE 6 Example Structure Name MS (M + 1) 219

3,4-dimethyl-2-(4-((1- methylcyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 330 219A

2-((3S,4S)-3-fluoro-4- ((1- methylcyclopropyl) methoxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 220

2-(4-((6-(2- methoxyethoxy)pyridin- 3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 413 220A

3,4-dimethyl-2-(4-((5- methylpyridin-3- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 353 221

3-cyclopropyl-2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 381 222

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)- 3-vinyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 341 223

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-5-oxo-6,7-dihydro-5H- pyrrolo[3,4-b]pyridine- 3-carbonitrile 366 224

4-methyl-2-(4-((1- methylcyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 316 225

2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 398 226

3-bromo-2-(4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 430, 432 227

2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 381

Example 228

3-Ethyl-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 7)

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(53 mg, 0.145 mmol, Example 222 in MeOH (10 mL) was added Pd/C (10%, 154mg, 0.145 mmol). The reaction was stirred under an atmosphere ofhydrogen (15 psi) at 15° C. for 1 h. The mixture was filtered and thefiltrate was concentrated in vacuo. The residue was purified by reversephase HPLC (ACN/water with 0.1% TFA modifier) to give the titlecompound. MS: 369 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.19 (1H, s),7.86 (1H, d, J=2.4 Hz), 7.52 (1H, dd, J=2.8 Hz, 9.2 Hz), 6.85 (1H, d,J=8.8 Hz), 4.52-4.53 (1H, m), 4.35 (2H, s), 3.89 (3H, s), 3.51-3.55 (2H,m), 3.15-3.19 (2H, m), 2.76 (2H, q, J=7.2 Hz), 2.13-2.16 (2H, m),1.91-1.95 (2H, m), 1.31 (3H, t, J=7.2 Hz).

The following example in table 7 were prepared according to scheme 7using the procedure and conditions outlined in the synthesis of Example228.

TABLE 7 Example Structure Name MS (M + 1) 229

3-ethyl-2-(4-((1- methylcyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 330 229A

4-ethyl-2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 383

Example 230

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-(trifluoromethyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 8)

To a solution of3-bromo-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(20 mg, 0.048 mmol) in DMF (1 mL) was added methyl2,2-difluoro-2-(fluorosulfonyl)acetate (12.83 mg, 0.067 mmol) andcopper(I) iodide (4.54 mg, 0.024 mmol) at 15° C. The resulting mixturewas stirred at 90° C. under microwave irradiation for 30 min. Afterfiltration and concentration, the residue was purified by reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to affort the title compound.MS: 409 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 8.26 (1H, s), 7.86 (1H,d, J=2.8 Hz), 7.49 (1H, dd, J=9.2, 2.8 Hz), 6.82 (1H, d, J=9.2 Hz),4.53-4.55 (1H, m), 4.42 (2H, s), 3.88 (3H, s), 3.75-3.80 (2H, m),3.40-3.45 (2H, m), 2.08-2.14 (2H, m), 1.86-1.90 (2H, m).

Example 231

6-(2-Hydroxyethyl)-3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 9) Step 1:6-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(120 mg, 0.339 mmol, Example 5) in DMSO (5 mL) was added lithiumbis(trimethylsilyl)amide (0.339 mL, 0.339 mmol) at RT. The reaction wasstirred for 20 min before (2-bromoethoxy)(tert-butyl)dimethylsilane (81mg, 0.339 mmol) was added. The reaction was stirred for 4 h and themixture was directly purified by reverse phase HPLC (ACN/water with 0.1%TFA modifier) to yield the title compound. MS: 482 (M+1).

Step 2:6-(2-Hydroxyethyl)-3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of6-(2-((tert-butyldimethylsilyl)oxy)ethyl)-3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(141 mg, 0.293 mmol) in THF (8 mL) was treated with TBAF (221 mg, 0.846mmol) at RT for 8 h. The volatiles were removed under reduced pressureand the residue was purified by silica gel column chromatography (15%MeOH in DCM) to yield the title compound. MS: 368 (M+1). ¹H NMR (500MHz, CDCl₃): δ 7.75 (s, 1H), 7.30 (t, J=9.0 Hz, 2H), 6.96-6.94 (m, 3H),4.54 (m, 1H), 4.41 (s, 2H), 3.91 (q, J=5.0 Hz, 2H), 3.76 (t, J=5.0 Hz,2H), 3.55 (m, 2H), 3.17 (m, 2H), 2.35 (s, 3H), 2.12 (m, 2H), 1.97 (m,2H).

Example 232

6-Ethyl-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 9)

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(100 mg, 0.282 mmol, Example 1) in DMSO (5 mL) was added lithiumbis(trimethylsilyl)amide (0.423 mL, 0.423 mmol, 1 M in THF). Thereaction was stirred at RT for 20 min and iodoethane (0.068 mLl, 0.846mmol) was added. The mixture was diluted with water (30 mL), extractedwith EtOAc (50 mL×3), and the combined organic layers were washed withwater (30 mL) and brine (30 mL), dried over anhydrous sodium sulfate,filtered and concentrated. The resultant residue was puritifed byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to provide thetitle compound. MS: 383 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.81(1H, d, J=2.8 Hz), 7.74 (1H, s), 7.42 (1H, dd, J=8.8, 3.2 Hz), 6.74 (1H,d, J=8.8 Hz), 4.47-4.52 (1H, m), 4.37 (s, 2H), 3.83 (s, 3H), 3.50-3.65(4H, m), 3.10-3.20 (2H, m), 2.36 (3H, s), 2.09-2.15 (2H, m), 1.80-1.91(2H, m), 1.24 (3H, t, J=7.2 Hz).

Example 233

6,7-Diethyl-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 9)

From the same reaction as described in the procedure for Example 232(vide supra) was obtained the title compound. MS: 411 (M+1). ¹H NMR (400MHz, methanol-d₄): δ 7.81 (1H, d, J=2.4 Hz), 7.74 (1H, s), 7.41 (1H, dd,J=8.8, 2.8 Hz), 6.74 (1H, d, J=9.2 Hz), 4.40-4.55 (2H, m), 3.83-3.89(1H, m), 3.57 (s, 3H), 3.45-3.55 (2H, m), 3.10-3.23 (3H, m), 2.13 (3H,s), 2.10-2.42 (3H, m), 1.78-1.99 (3H, m) 1.22 (3H, t, J=6.8 Hz), 0.55(3H, t, J=6.4 Hz).

Examples 234A and 234B

(S)-2-(4-((6-Ethoxypyridin-3-yl)oxy)piperidin-1-yl)-7-(2-hydroxyethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-2-(4-((6-ethoxypyridin-3-yl)oxy)piperidin-1-yl)-7-(2-hydroxyethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 9) Step 1:7-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-2-(4-((6-ethoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

2-(4-((6-Ethoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(0.87 g, 2.361 mmol) was dissolved in degassed DMSO (15.7 mL). LHMDS(1.5 M in THF, 2.36 mL, 3.54 mmol) was added dropwise to the solution at0° C. under a nitrogen atmosphere. The reaction was allowed to warm toRT and was sonicated before the addition of(2-bromoethoxy)(tert-butyl)dimethylsilane (0.760 mL, 3.54 mmol). Afterstirring for 90 min, the reaction was quenched with saturated, aqueousammonium chloride and was diluted with dichloromethane. The organic wasseparated, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (15-20% 3:1 EtOAc:EtOH in hexanes) toafford the title compound. MS: 527 (M+1).

Step 2:2-(4-((6-Ethoxypyridin-3-yl)oxy)piperidin-1-yl)-7-(2-hydroxyethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of7-(2-((tert-butyldimethylsilyl)oxy)ethyl)-2-(4-((6-ethoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(358 mg, 0.680 mmol) in THF (1 mL) was added TBAF (1.36 mL, 1.36 mmol).The reaction was stirred at RT for 15 h and was then concentrated todryness. The residue was purified by silica gel column chromatography(10-60% 3:1 EtOAc:EtOH in hexanes) to afford the title compound. Themixture of the two stereoisomers was purified by chiral SFC (OJ-Hcolumn, 30% methanol/CO₂) to afford isomer 234A (faster eluting): MS:413 (M+1). ¹H NMR (500 MHz, CDCl₃) δ 7.84 (1H, d, J=15.31 Hz), 7.27 (1H,s), 6.71 (1H, d, J=8.67 Hz), 6.19 (1H, s), 4.56 (1H, s), 4.39 (1H, s),4.33 (2H, d, J=7.78 Hz), 4.00 (2H, d, J=38.9 Hz), 3.56 (2H, br s), 3.17(2H, d, J=11.5 Hz), 2.37 (3H, s), 1.95-2.12 (6H, m), 1.40 (3H, t, J=7.11Hz). Isomer 234B (slower eluting): MS: 413 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 7.82-7.86 (1H, m), 7.24-7.26 (1H, m), 6.97 (1H, br s), 6.69(1H, d, J=8.92 Hz), 4.56 (1H, t, J=6.86 Hz), 4.37-4.39 (1H, m), 4.30(2H, q, J=7.07 Hz), 4.00-4.05 (2H, m), 3.92-3.96 (2H, m), 3.52-3.55 (2H,br m), 3.12-3.18 (2H, m), 2.36 (3H, s), 2.12 (2H, br s), 2.05 (2H, d,J=6.13 Hz), 1.95 (2H, br s), 1.39 (3H, t, J=7.05 Hz).

The following examples in table 9 were prepared according to scheme 9using the procedure and conditions outlined in the synthesis of Examples231, 232, 233, 234A and 234B. Commerically available alkyl halides areused in step 1. The final step is omitted in cases where there is nosilyl protecting group present in the compound.

TABLE 9 Example Structure Name MS (M + 1) 235

6-(2- (dimethylamino)ethyl)- 2-(4-((6- methoxypyridin-3-yl)oxy)piperidin-1-yl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 426 236

3-((1-(6-(2- (dimethylamino)ethyl)- 3-methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 420 236A

2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 411 237

2-((3S,4R)-3-fluoro-4- phenoxypiperidin-1- yl)-6-(2-hydroxyethyl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 386 238

6-(2-hydroxyethyl)-2- (4-((6-methoxypyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 399 238A¹

(R) or (S)-2-(4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)piperidin-1-yl)-6-(2- hydroxypropyl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 413 239

3-((1-(6-(2- hydroxyethyl)-3- methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 393 239A

6-(2-hydroxyethyl)-3- methyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 422240

3,6-dimethyl-2-(4- phenoxypiperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 338 240A

3-ethyl-2-((3S,4R)-3- fluoro-4-((1-methyl- 1H-indazol-5-yl)oxy)piperidin-1-yl)- 6-(2-hydroxyethyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 454 241

2-((3S,4R)-3-fluoro-4- phenoxypiperidin-1- yl)-3,6-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 356 241A

2-((3R,4R)-3-fluoro-4- ((1-methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 440 242

3-((1-(6-ethyl-3- methyl-5-oxo-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-2-yl)piperidin-4- yl)oxy)benzonitrile 377 243

6-ethyl-3-methyl-2-(4- phenoxypiperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 352 244

6-ethyl-2-((3S,4R)-3- fluoro-4- phenoxypiperidin-1- yl)-3-methyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 370 244A

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-6-ethyl-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 394 245

6-isopropyl-2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 397 246

3-((1-(6-isopropyl-3- methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 391 247

6-isopropyl-3-methyl- 2-(4-phenoxypiperidin- 1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 366 248

2-((3S,4R)-3-fluoro-4- phenoxypiperidin-1- yl)-6-isopropyl-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 384 249

3-((1-(6-cyclopropyl-3- methyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 389 250

6-cyclopropyl-3- methyl-2-(4- phenoxypiperidin-1- yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 364 250A

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6-(oxetan-3- ylmethyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 425 251

6-(3-methoxypropyl)- 2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 427 252

6-(2-methoxyethyl)-2- (4-((6-methoxypyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 382 253

2-(4-(4- fluorophenoxy)piperidin- 1-yl)-3,6-dimethyl- 6,7-dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 356 254

2-(4-((6-ethoxypyridin- 3-yl)oxy)piperidin-1- yl)-6-(2-hydroxyethyl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 413 255

2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-6- (2-hydroxyethyl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 255A

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)- 3-methyl-6,7-bis(oxetan-3-ylmethyl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 495256

methyl 2-(3,4- dimethyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)-5- oxo-5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)acetate 402 257

2-((3R,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-6- (2-hydroxyethyl)-3- methyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 258

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-3-ethyl-6-(2- hydroxyethyl)-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 424 259

2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6-(pyridin-4- ylmethyl)-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 446 259A

2-(4-((2,2-difluoro-1- methylcyclopropyl) methoxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 260

methyl 2-(2-(4-((6- methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5,7- dihydro-6H- pyrrolo[3,4-b]pyridin- 6-yl)acetate 427260A

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-6-(2-methoxyethyl)- 3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 438 261

2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-6- (2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 442 262

2-((3S,4R)-3-fluoro-4- (4- fluorophenoxy)piperidin- 1-yl)-6-(2-hydroxyethyl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 404263

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 263A

2-(4-((1,3-dihydro-2- benzofuran-5- yl)oxy)piperidin-1-yl)-6-(2-methoxyethyl)-3- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 424 ¹Protected bromide electrophile may be preparedaccording to literature procedure, see e.g.: Duffield, J. J.; Pettit, G.R. J. Nat. Prod. 2001, 10, 472-479.

Example 264

2-(4-(4-Fluorophenoxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 10) Step 1:2-(2-(4-(4-Fluorophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)aceticAcid

To a solution of2-(4-(4-fluorophenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(120 mg, 0.352 mmol, Example 72) and methyl 2-bromoacetate (215 mg,1.406 mmol) in THF (5 mL) was added NaH (42.2 mg, 1.055 mmol). Thereaction was stirred at 20° C. for 15 h after which time an aqueoussolution of NaOH (20%, 1.45 g, 7.26 mmol) was added. After stirring thereaction for an additional 2 h at RT, aqueous 2N HCl was added to pH˜4and the mixture was extracted with DCM (10 mL×3). The combined organiclayers were washed with water (20 mL×3), dried with anhydrous Na₂SO₄,filtered and the filtrate was evaporated under reduced pressure to yieldthe title compound. MS: 400 (M+1).

Step 2:2-(4-(4-Fluorophenoxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(2-(4-(4-fluorophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)aceticacid (150 mg, 0.376 mmol) in THF (5 mL) was added BH₃.DMS (2 M in THF,0.357 mL, 3.76 mmol). The reaction was stirred at 15° C. for 15 h beforequenching with MeOH (5 mL) and then concentrating the mnixture todryness. The residue was The residue was purified by reverse phase HPLC(ACN/water with 0.1% NH₃OH modifier) to give the title compound. MS: 386(M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.77 (1H, s), 6.95-7.07 (2H, m),6.84-6.95 (2H, m), 4.45 (1H, d, J=3.91 Hz), 4.42 (s, 2H), 3.90-3.92 (2H,m), 3.73-3.81 (2H, m), 3.48-3.60 (2H, m), 3.11-3.21 (2H, m), 3.03 (1H,br s), 2.35 (3H, s), 2.07-2.17 (2H, m), 1.90-1.99 (2H, m).

Example 264A

2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 10) Step 1: Methyl2-(2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate

To a solution of2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(1.68 g, 4.43 mmol) in degassed DMSO (29.5 mL) was added LHMDS (1.5 M inTHF, 3.54 mL, 5.31 mmol) at RT. After aging the solution for 15 min,methyl bromoacetate (0.813 g, 5.31 mmol) was added dropwise as asolution in THF (2 mL) under an atmosphere of nitrogen. After stirringfor 15 min, the reaction mixture was quenched with water (50 mL) andextracted with DCM (3×100 mL). The combined organic layers were driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (10-30% 3:1 EtOAc:EtOH in hexanes) to yield the titlecompound. MS: 452 (M+1).

Step 2:2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To an ice cold solution of methyl2-(2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate(273 mg, 0.605 mmol) in THF (3.0 mL) was added lithium borohydride (39.5mg, 1.814 mmol). The reaction was stirred at 0° C. for 10 min and wasstirred at 15° C. for 1 h. The reaction was slowly quenched with waterand was then diluted with EtOAc and aqueous saturated solution ofRochelle's salt. The organic layer was separated, dried over anhydroussodium sulfate, filtered and then concentrated to dryness. The materialwas purified by SFC (OJ-H column, 30% MeOH/CO₂) to afford the titlecompound. MS: 424 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.14 (d, J=8.2 Hz,1H), 6.86 (d, 1H), 6.82 (s, 1H), 5.07 (d, 4H), 4.53-4.44 (m, 1H), 4.35(s, 2H), 3.89 (s, 2H), 3.75 (t, J=5.0 Hz, 2H), 3.51-3.42 (m, 2H),3.13-3.04 (m, 3H), 2.62 (s, 3H), 2.23 (s, 3H), 2.13 (s, 2H), 2.01-1.91(m, 2H).

Examples 264B and 264C

(R)-6-(1-Hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-6-(1-hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 10) Step 1: Methyl2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(153 mg, 0.432 mmol) in degassed DMSO (2 mL) was added LHMDS (1.5 M inTHF, 0.35 mL, 0.525 mmol) at 0° C. The mixture was allowed to warm to RTand was stirred for 15 min before the addition of methyl2-bromoproprionate (0.072 mL, 0.648 mmol). The reaction was stirred for2 h at RT and was then cooled in an ice bath before quenching withsaturated aqueous ammonium chloride. EtOAc was used to extract thematerial and the organic was washed with water, then brine, dried overanhydrous sodium sulfate, filtered and concentrated. The resultantresidue was purified by silica gel chromatography (15-60% EtOAc inhexanes) to furnish the title compound. MS: 441 (M+1)

Step 2:(R)-6-(1-Hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-6-(1-hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Methyl2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)propanoate(103 mg, 0.234 mmol) was dissolved in THF (2 mL) under a nitrogenatmosphere. After cooling the system to 0° C., LiBH₄ (20.4 mg, 0.935mmol) was added and the reaction was allowed to warm gradually to RT.The reaction was quenched with saturated aqueous ammonium chloride at 0°C. and partitioned with EtOAc. The organic layer was washed with brine,dried over anhydrous sodium sulfate, filtered and concentrated. Theresultant residue was purified by silica gel chromatography (10-40% 3:1EtOAc:EtOH in hexanes). The racemate was resolved by chiral SFC (ADcolumn, 30% EtOH/CO₂) to afford isomer 264B (faster eluting): MS: 413(M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.87 (s, 1H), 7.73 (s, 1H), 7.26 (s,1H), 6.70 (d, 1H), 4.35 (m, 4H), 3.90 (s, 3H), 3.85 (m, 1H), 3.72 (m,1H), 3.52 (br s, 2H), 3.10 (br s, 2H), 2.32 (s, 3H), 2.09 (br s, 2H),1.92 (br s, 2H), 1.31 (d, 3H). Isomer 264C (slower eluting): MS: 413(M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.87 (s, 1H), 7.73 (s, 1H), 7.26 (s,1H), 6.70 (d, 1H), 4.35 (m, 4H), 3.90 (s, 3H), 3.85 (m, 1H), 3.72 (m,1H), 3.52 (br s, 2H), 3.10 (br s, 2H), 2.32 (s, 3H), 2.09 (br s, 2H),1.92 (br s, 2H), 1.31 (d, 3H).

The following examples in table 10 were prepared according to scheme 10using the procedure and conditions outlined in the synthesis of Examples264, 264A, 264B, and 264C In cases where the ester is saponified, thereduction step maybe omitted.

TABLE 10 Example Structure Name MS (M + 1) 264D 264E

(R)-2-(4-((2-hydroxy- 2,3-dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one and (S)-2-(4-((2-hydroxy-2,3-dihydro-1H-inden- 5-yl)oxy)piperidin-1- yl)-6-(2-hydroxyethyl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 438 265

6-(2-hydroxyethyl)-3,4- dimethyl-2-(4- phenoxypiperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 382 265A

2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)- 3-ethyl-6-(2-hydroxyethyl)-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424 265B265C

(R)-2-(4-((2,2-difluoro- 1- methylcyclopropyl)methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one and (S)-2-(4-((2,2-difluoro- 1-methylcyclopropyl) methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-3,4-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 410 410 265D

6-(2-hydroxyethyl)-3,4- dimethyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 436265E

6-(2-hydroxyethyl)-2- (4-(isochroman-7- yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 424 265F

6-(2-hydroxyethyl)-2- (4-(isochroman-6- yloxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 266

2-(4-(4- fluorophenoxy) piperidin-1-yl)-6-(2- hydroxyethyl)-3,4-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 400 266A

2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 424 266B

2-(2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-3,4-dimethyl-5-oxo- 5,7-dihydro-6H- pyrrolo[3,4-b]pyridin- 6-yl)aceticacid 438 266C 266D

(R)-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-6-(1-hydroxypropan-2- yl)-3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one and (S)-2-(4-((1,3-dihydro- 2-benzofuran-5-yl)oxy)piperidin-1-yl)- 6-(1-hydroxypropan-2- yl)-3,4-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 438 266E

3-ethyl-2-((3S,4S)-3- fluoro-4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 392 266F

3-ethyl-6-(2- hydroxyethyl)-2-(4- (isochroman-6- yloxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 266G

2-((3S,4S)-3-fluoro-4- ((1- methylcyclopropyl)methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 392 267

6-(2-hydroxyethyl)-3,4- dimethyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one374 267A

3-ethyl-6-(2- hydroxyethyl)-2-(4- (isochroman-7- yloxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 267B

2-(4- (cyclobutylmethoxy) piperidin-1-yl)-6-(2- hydroxyethyl)-3,4-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 374 267C 267D

(R)-6-(2- hydroxyethyl)-2-(4-((2- methoxy-2,3-dihydro- 1H-inden-5-yl)oxy)piperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one and (S)-6-(2-hydroxyethyl)-2-(4-((2-methoxy-2,3- dihydro-1H-inden-5- yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 452 452 267E

2-((3S,4R)-3-fluoro-4- ((1-methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)- 3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 440 267F

2-((3R,4R)-3-fluoro-4- ((1- methylcyclopropyl)methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 392 268

3-ethyl-6-(2- hydroxyethyl)-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one374 268A

3-ethyl-6-(2- hydroxyethyl)-2-(4-((1- methyl-1H-indazol-6-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 436268B

6-(2-hydroxyethyl)-2- (4-(isochroman-7- yloxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 268C 268D

(R)-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-6-(1-hydroxypropan-2- yl)-3-methyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one and (S)-2-(4- ((1,3-dihydro-2-benzofuran-5- yl)oxy)piperidin-1-yl)- 6-(1-hydroxypropan-2-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424 424 268E

2-((3S,4R)-3-fluoro-4- ((1-methyl-1H-indazol- 5-yl)oxy)piperidin-1-yl)-6-(2-hydroxyethyl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 454 268F

2-((3S,4R)-3-fluoro-4- ((1- methylcyclopropyl)methoxy)piperidin-1-yl)-6- (2-hydroxyethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 392

Example 269

6-Cyclopropyl-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 11)

The mixture of acetoxycopper (18.16 mg, 0.148 mmol),2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(50 mg, 0.141 mmol, Example 1), cyclopropylboronic acid (36.4 mg, 0.423mmol), DMAP (51.7 mg, 0.423 mmol) in toluene (5 mL) was added NaHMDS(0.141 mL, 0.141 mmol). The reaction was stirred at 80° C. under an O₂atmosphere for 6 h. The mixture was diluted with EtOAc (20 mL), quenchedwith water (10 mL) and acidified with aqueous 1 M HCl (10 mL). Theaqueous phase was extracted with EtOAc (10 mL×3). The combined organiclayers were washed with aqueous 1 M HCl and brine (10 mL) and dried overanhydrous sodium sulfate. The solvent was evaporated in vacuo and theresidue was purified by reverse phase HPLC (ACN/water with 0.1% TFAmodifier) to give the title compound. MS: 395 (M+1). ¹H NMR (400 MHz,methanol-d₄): δ 7.89 (s, 1H), 7.74 (s, 1H), 7.58 (dd, J=9.20, 2.80 Hz,1H), 6.91 (d, J=9.20 Hz, 1H), 4.52-4.55 (m, 1H), 4.31 (s, 2H), 3.91 (s,3H), 3.50-3.64 (m, 2H), 3.11-3.25 (m, 2H), 2.82-2.98 (m, 1H), 2.38 (s,3H), 2.04-2.21 (m, 2H), 1.82-1.97 (m, 2H), 0.80-0.97 (m, 4H).

Example 270

7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 12) Step 1:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(1 g, 2.82 mmol, Example 1) in THF (18.8 mL) at 0° C. was added SEM-Cl(1.0 mL, 5.64 mmol). The system was evacuated and placed under anatmosphere of nitrogen and NaH (60%, 0.226 g, 5.64 mmol) was added.After the addition, the reaction was allowed to warm up to RT. Themixture was quenched with aqueous sodium carbonate and was diluted withdichloromethane. The organic was separated, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by silica gel chromatography (EtOAc/hexanes) to yield thetitle compound. MS: 485 (M+1).

Step 2:7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(472.6 mg, 0.975 mmol) in THF (5 mL) at −78° C. was degassed and placedunder an atmosphere of nitrogen. LDA (2 M in THF, 1.46 mL, 2.93 mmol)was added dropwise and the reaction was aged 15 min.(1H-Benzo[d][1,2,3]triazol-1-yl)methanol (291 mg, 1.950 mmol) was addedas slurry in THF (1.5 mL) to the reaction at −78° C. and the reactionwas aged for 2 h. The reaction was quenched with water and waspartitioned with DCM (50 mL). The organic layer was washed with aqueous1 M NaOH and brine, dried over anhydrous sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel (10-80% EtOAc in hexanes) to provide the title compound.MS: 515 (M+1).

Step 3:7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(178 mg, 0.346 mmol) in DCM (2.3 mL) was added TFA (1.15 mL). Thereaction was stirred for 1 h at RT. Concentrate solution and neutralizewith saturated aqueous sodium bicarbonate and dilute with DCM. Theorganic was separated, dried over anhydrous sodium sulfate, filtered,and concentrated under reduced pressure. The residue was diluted withMeOH (2 mL) and Hunig's base (144 μL, 0.824 mmol) and the reaction washeated to 100° C. for 1 h. The mixture was diluted with water anddichloromethane. The organic was separated, dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas purified by column chromatography on silica gel (10-90% 3:1EtOAc:EtOH in hexanes) to provide the title compound. MS: 385 (M+1). ¹HNMR (500 MHz, CDCl₃): δ 7.90 (1H, d, J=3.00 Hz), 7.77 (1H, s), 7.36 (1H,br s), 7.28-7.30 (1H, m), 6.73 (1H, d, J=8.90 Hz), 4.62 (1H, s),4.39-4.42 (1H, m), 4.04 (1H, br s), 3.93 (3H, s), 3.87 (1H, br s), 3.60(2H, d, J=11.31 Hz), 3.18-3.22 (2H, m), 2.35 (3H, s), 2.13 (2H, br s),1.96 (2H, br s).

Examples 271A and 271B

(R)-7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(271A) and(S)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(271B) (Scheme 12)

7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Example 270) from the procedure for Example 270 (vide supra) wasresolved by chiral SFC (AS-H column, 30% MeOH with 0.1% DEA/CO₂) toafford isomer 271A (faster eluting, R-isomer): MS: 385 (M+1). ¹H NMR(500 MHz, CDCl₃): δ 7.90 (1H, d, J=2.94 Hz), 7.78 (1H, s), 7.28-7.30(1H, m), 7.14 (1H, s), 6.73 (1H, d, J=8.91 Hz), 4.62 (1H, s), 4.39-4.42(1H, m), 4.01 (1H, dd, J=10.85, 5.58 Hz), 3.93 (3H, s), 3.88 (1H, t,J=8.38 Hz), 3.59-3.61 (2H, m), 3.17-3.23 (2H, m), 2.36 (3H, s), 2.14(2H, br s), 1.96 (2H, dt, J=12.40, 6.48 Hz). Isomer 271B (slowereluting, S-isomer): MS: 385 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (1H,d, J=3.00 Hz), 7.77 (1H, s), 7.36 (1H, br s), 7.28-7.30 (1H, m), 6.73(1H, d, J=8.90 Hz), 4.62 (1H, s), 4.39-4.42 (1H, m), 4.04 (1H, br s),3.93 (3H, s), 3.87 (1H, br s), 3.60 (2H, d, J=11.31 Hz), 3.18-3.22 (2H,m), 2.35 (3H, s), 2.13 (2H, br s), 1.96 (2H, br s).

Example 272

6-(Hydroxymethyl)-3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 12) Step 1:3-Methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

SEM-Cl (0.141 mL, 0.795 mmol) was added to a stirred mixture of3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(200 mg, 0.530 mmol) in DMF (8 mL) at 0° C. NaH (42.4 mg, 1.06 mmol) wasadded and the reaction was stirred at 0° C. for 1 h. The reaction waswarmed to RT and was partioned with saturated NH₄Cl (aq) and EtOAc (10mL×3). The combined organic layers were dried over anhydrous sodiumsulfate, filtered and concentrated in vacuo. The residue was purified bysilica gel chromatography (1/1 EtOAc/petroleum ether) to afford thetitle compound. MS: 508 (M+1).

Step 2:6-(Hydroxymethyl)-3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(20 mg, 0.039 mmol) in THF (2 mL) was added LDA (1 M in THF, 0.039 mL,0.079 mmol) at −65° C. under a nitrogen atmosphere. After stirring for 1h at −65° C., (1H-benzo[d][1,2,3]triazol-1-yl)methanol (5.88 mg, 0.039mmol) was added to the mixture. After an additional 1 h at thistemperature, the reaction was warmed to RT and was directly purified byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to give the titlecompound. MS: 408 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.86 (1H, s),7.78 (1H, s), 7.45 (1H, d, J=9.2 Hz), 7.15 (1H, s), 7.13 (1H, dd, J=9.2,2.4 Hz), 4.96 (2H, s), 4.59-4.61 (1H, m), 4.43 (2H, s), 4.01 (3H, s),3.59-3.62 (2H, m), 3.212-3.25 (2H, m), 2.37 (3H, s), 2.14-2.17 (2H, m),1.92-1.95 (2H, m).

Examples 273A and 273B

(R)-7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(273A) and(S)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(273B) (Scheme 13)

A solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(96 mg, 0.261 mmol, Example 18) in THF (1.3 mL) at −78° C. was degassedand placed under an atmosphere of nitrogen. LDA (2 M in THF, 391 μL,0.782 mmol) was added dropwise at −78° C. and the reaction was aged 15min. 1H-Benzo[d][1,2,3]triazol-1-yl)methanol (78 mg, 0.521 mmol) wasadded as a slurry in THF (0.4 mL) to the reaction at −78° C. and thereaction was aged for 1 h at this temperature. The reaction was quenchedwith water and was extracted with chloroform. The organic layer wasdried over anhydrous sodium sulfate, filtered, and concentrated invacuo. The residue was purified by column chromatography on silica gel(15-40% 3:1 EtOAc:EtOH in hexanes) to yield the racemate. The titlecompounds were resolved by chiral SFC (AS-H column, 40% MeOH with 0.1%DEA/CO₂) to afford isomer 273A (faster eluting, R-isomer): MS: 399(M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.86 (1H, s), 7.70 (1H, s), 6.70 (1H,d, J=8.99 Hz), 4.38 (1H, s), 4.31 (1H, s), 4.19 (2H, s), 3.90 (3H, d,J=2.34 Hz), 3.81 (1H, t, J=8.83 Hz), 3.54 (4H, br s), 3.13-3.15 (4H, m),2.31 (3H, s), 2.11 (2H, br s), 1.93 (2H, br s). Isomer 273B (slowereluting, S-isomer): MS: 399 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.86 (1H,s), 7.71 (1H, s), 6.71 (1H, d, J=9.02 Hz), 4.38 (1H, s), 4.32 (1H, s),4.19 (2H, br s), 3.90 (3H, d, J=2.29 Hz), 3.80 (1H, t, J=9.41 Hz), 3.53(4H, br s), 3.14 (4H, br s), 2.31 (3H, s), 2.11 (2H, br s), 1.94 (2H, brs).

Example 274

7,7-Bis(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 13)

From the same reaction as described in the procedure for Examples 273Aand 273B (vide supra) was obtained the title compound. MS: 429 (M+1). ¹HNMR (400 MHz, methanol-d₄): δ 7.83 (1H, d, J=3.00 Hz), 7.70 (1H, s),7.42 (1H, dd, J=8.98, 3.04 Hz), 6.76 (1H, d, J=8.96 Hz), 4.47-4.51 (1H,m), 3.94 (4H, s), 3.85 (3H, s), 3.60-3.63 (3H, m), 3.22 (3H, br s), 3.11(3H, s), 2.35 (3H, s), 2.11-2.15 (3H, m), 1.86-1.93 (3H, m).

The following examples in table 13 were prepared according to scheme 13using the procedure and conditions outlined in the synthesis of Example273A, 273B and 274.

TABLE 13 Example Structure Name MS (M + 1) 275

(R)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4- phenoxypiperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 368 276

(S)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4- phenoxypiperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 368 277

(R)-2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-7- (hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 277A

(R)-2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 411 278

(S)-2-((3S,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-7- (hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 278A

(S)-2-(4-((5,7- dihydrofuro[3,4- b]pyridin-3- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 411 279

(S)-2-(4-(4- fluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,6-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 386 279A

(R)-2-((3R,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-7- (hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 280

(R)-2-(4-(4- fluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,6-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 386 280A

(S)-2-((3R,4R)-4-((1,3- dihydro-2-benzofuran- 5-yl)oxy)-3-fluoropiperidin-1-yl)-7- (hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 428 281

(S)-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 281A

(R)-2-((3R,4R)-3- fluoro-4-((6- methoxypyridin-3-yl)oxy)piperidin-1-yl)- 7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 417 282

(R)-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 282A

(S)-2-((3R,4R)-3- fluoro-4-((6- methoxypyridin-3-yl)oxy)piperidin-1-yl)- 7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 417 283

(S)-2-((3S,4R)-3- fluoro-4-((1-methyl- 1H-indazol-5-yl)oxy)piperidin-1-yl)- 7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 440 284

(R)-2-((3S,4R)-3- fluoro-4-((1-methyl- 1H-indazol-5-yl)oxy)piperidin-1-yl)- 7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 440 285

(R)-2-(4-((6- ethoxypyridin-3- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 413 286

(S)-2-(4-((6- ethoxypyridin-3- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 413

Examples 287A and 287B

(R)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(287A) and(S)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(287B) (Scheme 14)

A solution of7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(410 mg, 1.029 mmol) in THF (5 mL) at −78° C. was degassed and placedunder an atmosphere of nitrogen. LDA (2 M in THF, 2.06 mL, 4.12 mmol)was added at −78° C. the reaction was aged 15 min. MeI (0.257 mL, 4.12mmol) was added dropwise to the reaction at −78° C. and the reaction wasaged for 1 h at this temperature. The reaction was quenched with waterand was extracted with chloroform. The organic layer was dried overanhydrous sodium sulfate, filtered, and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel (10-60% 3:1EtOAc:EtOH in hexanes) to yield the racemate. The mixture of the twostereoisomers was purified by chiral SFC (AD-H column, 30% MeOH/CO₂) toafford isomer 287A (faster eluting, R-isomer): MS: 413 (M+1). ¹H NMR(500 MHz, acetone-d₆): δ 7.96 (1H, s), 7.66 (1H, s), 7.49 (1H, d, J=8.87Hz), 6.78 (1H, d, J=8.93 Hz), 4.59 (1H, s), 4.16 (1H, s), 3.97-3.93 (2H,m), 3.89 (3H, s), 3.64 (3H, br s), 3.23 (2H, q, J=11.14 Hz), 3.03 (4H,s), 2.39 (2H, s), 2.20 (2H, br s), 1.94 (2H, br s), 1.43 (2H, s). Isomer287B (slower eluting, S-isomer): MS: 413 (M+1). ¹H NMR (500 MHz,acetone-d₆): δ 7.94 (1H, d, J=2.90 Hz), 7.63 (1H, s), 7.46 (1H, dd,J=8.92, 2.92 Hz), 6.76 (1H, d, J=8.92 Hz), 4.55-4.58 (1H, m), 4.15 (1H,s), 3.88-3.97 (2H, m), 3.87 (3H, s), 3.62 (3H, br s), 3.21 (2H, q,J=11.23 Hz), 3.01 (4H, s), 2.36 (2H, s), 2.18 (2H, br s), 1.90-1.94 (2H,m), 1.41 (2H, s).

Example 288

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 15) Step 1:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,7,7-trimethyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(140 mg, 0.289 mmol) in THF (5 mL) was added iodomethane (123 mg, 0.867mmol) in a schlenk flask at 0° C. under an atmosphere of nitrogen.LiHMDS (2 M in THF, 0.433 mL, 0.867 mmol) was added dropwise to thereaction and the mixture was stirred at 0° C. for 30 min. Saturated,aqueous NH₄Cl (1 mL) and water (10 mL) were added and the solution wasextracted with EtOAc (10 mL×3). The organic layers were combined andconcentrated to provide the title compound, which was used withoutfurther purification. MS: 395 (M+1).

Step 2:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,7,7-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,7,7-trimethyl-6-((2-(trimethylsilypethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(50 mg, 0.098 mmol) in THF (3 mL) was added TBAF (1 M, 1.95 mL, 1.95mmol). The reaction was stirred at 70° C. for 48 h. Water (20 mL) andEtOAc (20 mL) were added and the organic was separated, washed withwater (10 mL×4), and concentrated under reduced pressure. The residuewas purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) togive the title compound. MS: 383 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ7.86 (1H, s), 7.68 (1H, s), 7.53 (1H, d, J=2.8 Hz), 6.87 (1H, d, J=9.2Hz), 4.47-4.53 (1H, m), 3.88 (3H, s), 3.50-3.60 (2H, m), 3.15-3.22 (2H,m), 2.33 (3H, s), 2.03-2.12 (2H, m), 1.84-1.89 (2H, m), 1.44 (6H, s).

Example 289

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7-methylene-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 16) Step 1:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7-methylene-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(153 mg, 0.297 mmol) in THF (991 μL) was added DBU (67.2 μL, 0.446mmol). The reaction was refluxed for 5 h and the reaction wasconcentrated to dryness to provide the title compound, which was usedwithout further purification. MS: 497 (M+1).

Step 2:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7-methylene-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-7-methylene-6-((2-(trimethylsilyl)ethoxy)methyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(148 mg, 0.297 mmol) was dissolved in 1/1 TFA/DCM (2 mL) and was stirredat RT for 2 h. The reaction was slowly quenched With aq. Saturatedsodium bicarbonate and aqueous 1 M NaOH. Partition and extract themixture with chloroform and dry the organic over anhydrous sodiumsulfate before concentration. Dilute residue with MeOH (1 mL) andHunig's base (400 uL) and heat for 1 h at 70° C. Remove solvent underreduced pressure and purify crude material by mass triggered reversephase HPLC (ACN/water with 0.1% NH₃OH modifier) to afford the titlecompound. MS: 367 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.84-7.90 (1H, m),7.74-7.78 (1H, m), 7.30 (1H, s), 6.69-6.75 (1H, m), 5.48-5.52 (1H, m),4.86-4.91 (1H, m), 4.36-4.44 (1H, m), 3.87-3.93 (3H, m), 3.56-3.65 (2H,m), 3.16-3.25 (2H, m), 2.33-2.39 (3H, m), 2.06-2.17 (2H, m), 1.86-2.02(2H, m).

Example 290

3-Methyl-2-(4-((2-methylisoindolin-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 17)

To a solution of2-(4-(isoindolin-5-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(50 mg, 0.105 mmol, Example 147) in THF (1 mL) was addedparaformaldehyde (40 mg, 0.105 mmol). The reaction was stirred at 40° C.for 0.5 h before sodium triacetoxyborohydride (44.3 mg, 0.209 mmol) wasadded. The mixture was stirred at 20° C. for 2 h and was thenconcentrated to dryness. The residue was purified by reverse phase HPLC(ACN/water with 0.1% TFA modifier) to afford the title compound. MS: 379(M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.78 (1H, s), 7.22 (1H, d, J=8.4Hz), 7.01-7.04 (2H, m), 4.87-4.89 (2H, m), 4.62-4.64 (1H, m), 4.30-4.57(4H, m), 2.64-2.56 (2H, m), 3.18-3.22 (2H, m), 3.10 (3H, s), 3.37 (3H,s), 2.12-2.15 (2H, m), 1.87-1.91 (2H, m).

The following examples in table 17 were prepared according to scheme 17using the procedure and conditions outlined in the synthesis of Example290.

TABLE 17 Example Structure Name MS (M + 1) 291

3-methyl-2-(4-((1- methyl-1,2,3,4- tetrahydroquinolin-6-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 393292

3-methyl-2-(4-((2- methyl-1,2,3,4- tetrahydroisoquinolin-7-yl)oxy)piperidin-1- yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one393 293

3-methyl-2-(4-((4- methyl-3,4-dihydro- 2H- benzo[b][1,4]oxazin-7-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 395

Example 294

2-(4-((2-Acetylisoindolin-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 18)

To a solution of2-(4-(isoindolin-5-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(20 mg, 0.042 mmol) and Et₃N (0.017 mL, 0.125 mmol) in DCM (2 mL) wasadded acetyl chloride (3.61 mg, 0.046 mmol) at 0° C. The reaction wasallowed to warm to RT and was stirred for an additional 1 h. Thereaction was concentrated to dryness and the residue was purified byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford thetitle compound. MS: 407 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.80(1H, s), 7.22 (1H, d, J=8.4 Hz), 6.96-6.98 (2H, m), 4.61-4.70 (5H, m),4.33 (2H, s), 3.56-3.59 (2H, m), 3.20-3.23 (2H, m), 2.39 (3H, s),2.15-2.17 (5H, m), 1.91-1.93 (2H, m).

The following examples in table 18 were prepared according to scheme 18using the procedure and conditions outlined in the synthesis of Example294.

TABLE 18 Example Structure Name MS (M + 1) 295

2-(4-((2-acetyl-1,2,3,4- tetrahydroisoquinolin- 7-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 421

Example 296

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(pyridin-4-ylmethyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(Scheme 19) Step 1:2-Cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinicAcid

To methyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate(485 mg, 1.268 mmol) in tetrahydrofuran (3.81 mL) and MeOH (1.27 mL) wasadded a solution of LiOH (60.7 mg, 2.54 mmol) in water (1.27 mL) at RT.The reaction was sonicated and stirred at RT and upon completion thesolution was neutralized to pH˜5 with aqueous 1 M HCl and was dilutedwith additional water and 2/1/1 DCM/THF/MeOH. The organic layer wasseparated, dried over anhydrous sodium sulfate and filtered beforeconcentrating to dryness. The title compound was used without furtherpurification. MS: 367 (M+1).

Step 2:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(pyridin-4-ylmethyl)-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

To a solution of2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinicacid (150 mg, 0.407 mmol) in DMA (1.36 mL) was added HATU (232 mg, 0.611mmol) and DIPEA (213 μL, 1.22 mmol). The mixture was sonicated and thenpyridin-4-ylmethanamine (52.8 mg, 0.489 mmol) was added to the solutionand the reaction was stirred at RT. Upon completion, the mixture wasquenched with water and was diluted with dichloromethane. The organicwas separated, dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was purified by columnchromatography on silica gel (20-70% 3:1 EtOAc:EtOH in hexanes) to givethe title compound as a minor product. MS: 369 (M+1). ¹H NMR (500 MHz,methanol-d₄): δ 8.49 (2H, d, J=5.31 Hz), 7.88 (1H, s), 7.85 (1H, d,J=3.07 Hz), 7.43 (1H, dd, J=8.95, 3.05 Hz), 7.40 (2H, d, J=5.12 Hz),6.76 (1H, d, J=8.94 Hz), 4.88 (2H, s), 4.53 (1H, tt, J=7.58, 3.73 Hz),3.86 (3H, s), 3.68-3.73 (2H, m), 3.32-3.35 (2H, m), 2.44 (3H, s),2.12-2.16 (2H, m), 1.86-1.93 (2H, m).

Example 297

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione(Scheme 19) Step 1:2-Cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)nicotinamide

From the same reaction as described in step 2 of the procedure in thesynthesis of Example 296 (vide supra) was obtained the title compound asthe major product. MS: 459 (M+1).

Step 2:6-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-3-((pyridin-4-ylmethyl)carbamoyl)picolinicAcid

To2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-N-(pyridin-4-ylmethyl)nicotinamide(179 mg, 0.390 mmol) in dioxane (781 μL) was added aqueous NaOH (1 M,781 μL, 0.781 mmol). The reaction was heated to 60° C. Upon completion,the reaction was cooled and neutralized to pH˜4 and diluted with DCM.The organic separated and was dried over anhydrous sodium sulfate,filtered and concentrated to dryness. The title compound was usedwithout further purification. MS: 478 (M+1).

Step 3:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5H-pyrrolo[3,4-b]pyridine-5,7(6H)-dione

To a mixture of6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methyl-3-((pyridin-4-ylmethyl)carbamoyl)picolinicacid (148.7 mg, 0.311 mmol) in DCM (1.56 mL) was added DMF (2.41 μL,0.031 mmol). The addition of oxalyl chloride (82 μL, 0.934 mmol)produced an exothermic reaction and the solution was stirred for 5 min.NaBH₄ (35.3 mg, 0.934 mmol) and MeOH (1 mL) were added to the mixtureand the reaction was stirred for 10 min before quenching with aqueous,saturated Rochelle's salt. The mixture was partitioned with DCM and theorganic was separated, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified by mass triggered reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to afford the title compound.MS: 483 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ 7.84-7.85 (2H, m), 7.44(1H, dd, J=8.95, 3.06 Hz), 6.76-6.78 (1H, m), 4.51-4.54 (1H, m), 3.87(3H, s), 3.66-3.71 (2H, m), 3.38-3.24 (2H, m), 2.44 (3H, s), 2.11-2.16(2H, m), 1.86-1.94 (2H, m).

Example 298

7-Hydroxy-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 19)

From the same reaction as described in the procedure of Example 297(vide supra) was obtained the title compound. MS: 485 (M+1). ¹H NMR (500MHz, methanol-d₄): δ 8.03 (1H, d, J=3.05 Hz), 7.92 (1H, dd, J=9.32, 3.31Hz), 7.78 (1H, s), 7.24 (1H, d, J=9.33 Hz), 5.78 (1H, s), 4.63-4.66 (1H,m), 4.06 (3H, s), 3.63 (2H, br s), 3.25-3.32 (2H, m), 2.39 (3H, s), 2.18(2H, br s), 1.95 (2H, br s).

Example 299

tert-Butyl2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridine-6-carboxylate(Scheme 20)

To2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(120 mg, 0.339 mmol, Example 1) in DCM (1.69 mL) was added DMAP (4.14mg, 0.034 mmol) and triethylamine (142 μL, 1.016 mmol). At 0° C. wasadded BOC-anhydride (118 μL, 0.508 mmol), and the reaction was allowedto warm to RT with stirring. After 24 h at RT, the mixture was dilutedwith water and chloroform. The organic was separated, dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was purified by column chromatography on silicagel (10-20% 3:1 EtOAc:EtOH in hexanes) to obtain the title compound. MS:456 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.90 (1H, d, J=3.00 Hz), 7.81 (1H,s), 7.27-7.28 (1H, m), 6.74 (1H, d, J=8.89 Hz), 4.66 (2H, s), 4.41-4.44(1H, m), 3.93 (2H, s), 3.63-3.67 (3H, m), 3.21-3.26 (2H, m), 2.37 (3H,s), 2.12-2.16 (2H, m), 1.93-1.99 (2H, m), 1.62 (9H, s).

Example 300

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methylspiro[cyclopropane-1,7-pyrrolo[3,4-b]pyridine-5-(6H)-one(Scheme 21)

In a 30 mL schlenk tube, a mixture of methyl2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-methylnicotinate(100 mg, 0.261 mmol), titanium(IV) isopropoxide (149 mg, 0.523 mmol) inTHF (3 mL) was prepared. Ethylmagnesium bromide (3 M, 0.18 mL, 0.523mmol) was added at 0° C. and the reaction was stirred at RT for 6 h. Themixture was diluted with water (10 mL) and extracted with EtOAc (10mL×3). The combined organic layers were dried over anhydrous magnesiumsulfate, filtered, and concentrated in vacuo. The residue was purifiedby reverse phase HPLC (ACN/water with 0.1% TFA modifier) to afford thetitle compound. MS: 381 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.87(1H, d, J=2.8 Hz), 7.75 (1H, s), 7.55 (1H, dd, J=9.2, 2.8 Hz), 6.88 (1H,d, J=9.2 Hz), 4.50-4.52 (1H, m), 3.90 (3H, s), 3.56-3.58 (2H, m),3.15-3.20 (2H, m), 2.35 (3H, s), 2.10-2.12 (2H, m), 1.86-1.88 (2H, m),1.53-1.56 (2H, m), 1.46-1.47 (2H, m).

Example 301

3-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 22)

DIBAL-H (1 M in DCM, 4.52 mL, 4.52 mmol) was added to a stirred mixtureof methyl2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carboxylate(180 mg, 0.452 mmol, Example 160) in THF (10 mL) at 0° C. After theaddition the reaction was allowed to warm to RT and was stirred for 1 h.The volatiles were removed under reduced pressure and the crude residuewas purified by column chromatography on silica gel (20/1 DCM/MeOH) togive the title compound. MS: 371 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ8.16 (1H, s), 7.84 (1H, d, J=3.0 Hz), 7.43 (1H, dd, J=9.0, 3.1 Hz), 6.76(1H, d, J=8.9 Hz), 4.65 (2H, s), 4.49-4.52 (1H, m), 4.36 (2H, s), 3.86(3H, s), 3.59-3.63 (2H, m), 3.21-3.26 (2H, m), 2.11-2.15 (2H, m),1.86-1.93 (2H, m).

The following examples in table 22A were prepared according to scheme 22using the procedure and conditions outlined in the synthesis of Example301.

TABLE 22A Example Structure Name MS (M + 1) 302

4-(hydroxymethyl)-2- (4-((6-methoxypyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 385

Example 304

3-(Fluoromethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 22)

DAST (0.018 mL, 0.135 mmol) was added to a stirred mixture of3-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(10 mg, 0.027 mmol, Example 301) in 1/1 DCM/CHCl₃ (6 mL) at −78° C. Thereaction was stirred at −78° C. for 1 h and was warmed to RT. Thereaction was directly purified by column chromatography on silica gel(20/1 DCM/MeOH) to give the title compound. MS: 373 (M+1). ¹H NMR (500MHz, CDCl₃): δ 8.14 (1H, s), 7.90 (1H, d, J=3.0 Hz), 6.73 (1H, d, J=8.9Hz), 6.28 (1H, s), 5.42 (2H, d, J=48.5 Hz), 4.40-4.42 (3H, m), 3.93 (3H,s), 3.66 (2H, t, J=9.3 Hz), 3.25-3.30 (2H, m), 2.12-2.15 (2H, m), 1.98(2H, m).

The following examples in table 22B were prepared according to scheme 22using the procedure and conditions outlined in the synthesis of Example304.

TABLE 22B Example Structure Name MS (M + 1) 305

4-(fluoromethyl)-2-(4- ((6-methoxypyridin-3- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 387

Example 306

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbaldehyde(Scheme 23)

DMP (34.4 mg, 0.081 mmol) was added to a stirred mixture of3-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(25 mg, 0.067 mmol, Example 301) in CHCl₃ (3 mL) at 0° C. The reactionwas stirred for 1 hr at 0° C. The mixture was directly purified bycolumn chromatography on silica gel (20/1 DCM/MeOH) to give the titlecompound. MS: 369 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 9.96 (1H, s), 8.40(1H, s), 7.89 (1H, d, J=3.0 Hz), 6.74 (1H, d, J=8.9 Hz), 6.54 (1H, s),4.49-4.52 (1H, m), 4.43 (2H, s), 3.86-3.92 (5H, m), 3.58-3.63 (2H, m),2.13-2.17 (2H, m), 1.97-2.03 (2H, m).

Example 307

3-(Difluoromethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 23)

DAST (0.065 mL, 0.489 mmol) was added to a stirred mixture of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-3-carbaldehyde(18 mg, 0.049 mmol, Example 306) in 1/1 DCM/CHCl₃ (6 mL) at −78° C. Thereaction was stirred at −78° C. for 1 h and was further aged for 2 h atRT. The reaction was quenched with MeOH and concentrated to be purifiedon silica gel by column chromatography to (10/1 DCM/MeOH) to give thetitle compound. MS: 391 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 8.32 (1H, s),7.87 (1H, m), 6.78 (1H, t, J=60 Hz), 6.71 (1H, d, J=8.9 Hz), 6.53 (1H,s), 4.44 (3H, m), 3.90 (3H, s), 3.30 (2H, m), 3.15 (2H, d, J=7.7 Hz),2.11 (2H, m), 1.99 (2H, m).

The following example in table 23 were prepared according to scheme 23using the procedure and conditions outlined in the synthesis of Examples306 and 307.

TABLE 23 Example Structure Name MS (M + 1) 307A

4-(difluoromethyl)-2- (4-((6-methoxypyridin- 3-yl)oxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 405

Example 308

3-((1-(3-Methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzaldehyde(Scheme 24)

DIBAL-H (1 M in DCM, 5.63 mL, 5.63 mmol) was added to a stirred mixtureof3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile(490 mg, 1.406 mmol, Example 3) in DCM (10 mL) at −78° C. The reactionwas aged for 1 h and was allowed to warm to RT. Saturated, aqueous NH₄Cland DCM were added to the reaction and the organic was separated, driedover anhydrous sodium sulfate and concentrated. The residue was purifiedby column chromatography on silica gel (20/1 DCM/MeOH) to provide thetitle compound. MS: 352 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 9.99 (1H, s),7.81 (1H, s), 7.47 (1H, d, J=4.8 Hz), 7.45 (1H, br s), 7.23 (1H, m),6.43 (1H, br s), 4.63-4.66 (1H, m), 4.38 (2H, s), 3.57 (2H, t, J=9.4Hz), 3.20-3.24 (2H, m), 2.37 (3H, s), 2.15-2.19 (2H, m), 1.96-2.02 (2H,m).

Example 309

2-(4-(3-(Hydroxymethyl)phenoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 24)

NaBH₄ (33.6 mg, 0.888 mmol) was added to a stirred mixture of3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzaldehyde(156 mg, 0.444 mmol, Example 308) in 1/1 MeOH/THF (6 mL) at 0° C. Thereaction was stirred for 15 min and was concentrated to dryness. Theresidue was purified by column chromatography on silica gel (20/1DCM/MeOH) to provide the title compound. MS: 354 (M+1). ¹H NMR (500 MHz,CDCl₃): δ 7.81 (1H, s), 6.94-6.99 (2H, m), 6.88 (1H, d, J=8.3 Hz), 6.24(1H, s), 4.69 (2H, s), 4.57 (1H, m), 4.37 (2H, s), 3.58 (2H, m), 3.20(2H, m), 2.37 (3H, s), 2.14 (2H, m), 1.98 (2H, m).

Example 310

2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)acetamide(Scheme 25)

To a solution of methyl2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate(20 mg, 0.047 mmol, Example 260) in MeOH (2 mL) was added ammoniumhydroxide (4.93 mg, 0.141 mmol) at 0° C. over 20 min. The mixture washeated to 20° C. and stirred for 2 h. The mixture was concentrated underreduce pressure. The residue was purified by reverse phase HPLC(ACN/water with 0.1% NH₃OH modifier) to give the title compound. MS: 412(M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.82 (1H, d, J=3.2 Hz), 7.77(1H, s), 7.41 (1H, dd, J=8.8, 2.8 Hz), 6.74 (1H, d, J=8.8 Hz), 4.46-4.52(1H, m), 4.41 (2H, s), 4.25 (2H, s), 3.84 (3H, s), 3.52-3.63 (2H, m),3.14-3.24 (2H, m), 2.37 (3H, s), 2.08-2.16 (2H, m), 1.83-1.94 (2H, m).

The following example in table 25 were prepared according to scheme 25using the procedure and conditions outlined in the synthesis of Example310.

TABLE 25 Example Structure Name MS (M + 1) 310A

2-(2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-3,4-dimethyl-5-oxo- 5,7-dihydro-6H- pyrrolo[3,4-b]pyridin-6-yl)acetamide 437

Example 311

2-(4-((2,2-Dimethylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 26) Step 1: 4-((2,2-Dimethylcyclopropyl)methoxy)piperidine

tert-Butyl 4-((2,2-dimethylcyclopropyl)methoxy)piperidine-1-carboxylate(25 mg, 0.059 mmol, intermediate L2) in HCl (2 M in EtOAc, 0.5 mL) wasstirred at 20° C. for 1 h. The reaction was concentrated to dryness toprovide the title compound, which was used without further purification.

Step 2: Methyl2-cyano-6-(4-((2,2-dimethylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (11.50 mg,0.055 mmol, intermediate A1) in DMF (1 mL) was added4-((2,2-dimethylcyclopropyl)methoxy)piperidine (20 mg, 0.055 mmol) andDIPEA (0.038 mL, 0.218 mmol). The reaction was stirred at 80° C. for 15h. After cooling the reaction to RT, it was poured into water (10 mL)and extracted with EtOAc (20 mL×3). The combined organic layers weredried over anhydrous Na₂SO₄, filtered and concentrated to provide thetitle compound, which was used without further purification. MS: 358(M+1).

Step 3:2-(4-((2,2-Dimethylcyclopropyl)methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-6-(4-((2,2-dimethylcyclopropyl)methoxy)piperidin-1-yl)-5-methylnicotinate(25 mg, 0.035 mmol) in MeOH (5 mL) was added ammonium hydroxide (0.024mL, 0.175 mmol) and Raney® nickel (25 mg, 0.426 mmol). The suspensionwas degassed and purged with hydrogen several times. The mixture wasstirred at 20° C. for 3 h under a hydrogen atmosphere (50 psi). Thesuspension was filtered and the filtrate was concentrated. The residuewas purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier) togive the title compound. MS: 330 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.78(1H, s), 6.26 (1H, s), 4.35 (2H, s), 3.50-3.61 (4H, m), 3.41-3.43 (1H,m), 2.90-3.03 (2H, m), 2.34 (3H, s), 1.95-2.05 (2H, m), 1.70-1.75 (2H,m), 1.11 (3H, s), 1.09 (3H, s), 0.80-0.91 (1H, m), 0.48-0.53 (1H, m),0.11-0.13 (1H, m).

The following examples in table 26 were prepared according to scheme 26using the procedure and conditions outlined in the synthesis of Example311. Alternative reaction conditions for step 1 includes the use of TFAas the reagent and DCM as the solvent or else exposure to Pd/C catalystunder a hydrogen atmosphere.

TABLE 26 Example Structure Name MS (M + 1) 311A

2-(4-((1-cyclopropyl- 1H-pyrazol-4- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 354 312

2-(4-((1- (hydroxymethyl) cyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 332 312A

2-(4-((1-(2- methoxyethyl)-1H- pyrazol-4- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 372 312B

2-(4-((1- hydroxycyclopropyl) methoxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 318

Example 313

2-(4-((3-Chloro-1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 27)

NCS (36.7 mg, 0.275 mmol) was added to a stirred mixture of2-(4-((1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(100 mg, 0.275 mmol, Example 167) in DMF (5 mL) at 0° C. The reactionwas stirred at RT for 15 h and then at 100° C. for 2 h. The volatilesremoved in vacuo and the residue was purified by column chromatographyon silica gel (20/1 DCM/MeOH) to afford the title compound as the majorproduct. MS: 398 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ 7.78 (1H, s),7.43 (1H, d, J=9.0 Hz), 7.17 (1H, d, J=9.2 Hz), 7.11 (1H, s), 4.66 (1H,s), 4.33 (2H, s), 3.59 (2H, t, J=9.3 Hz), 3.24 (2H, t, J=10.3 Hz), 2.38(3H, s), 2.18 (2H, m), 1.97 (2H, t, J=10.4 Hz).

Example 314

2-(4-((4-Chloro-1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 27)

From the same reaction as described in the procedure for Example 313(vide supra) was obtained the title compound. MS: 398 (M+1). ¹H NMR (500MHz, methanol-d₄): δ 8.03 (1H, s), 7.81 (1H, s), 7.48 (1H, d, J=8.9 Hz),7.36 (1H, d, J=9.0 Hz), 4.63 (1H, m), 4.35 (2H, s), 3.67 (2H, m), 3.23(2H, m), 2.40 (3H, s), 2.14 (2H, m), 2.01 (2H, m).

The following example in table 27 were prepared according to scheme 27using the procedure and conditions outlined in the synthesis of Example314.

TABLE 27 Example Structure Name MS (M + 1) 315

2-(4-((3-bromo-1H- indazol-5- yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 442, 444

Example 316

5-((1-(3-Methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)-1H-indazole-3-carbonitrile(Scheme 28)

Chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′-biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II)(4.27 mg, 5.43 μmol) was added to a stirred mixture of2-(4-((3-bromo-1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(24 mg, 0.054 mmol, Example 315) and dicyanozinc (12.74 mg, 0.109 mmol)in DMF (4 mL). The reaction was stirred at 200° C. for 30 min undermicrowave irradiation. The crude mixture was purified by reverse phaseHPLC (ACN/water with 0.1% TFA modifier) to provide the title compound.MS: 389 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.83 (1H, s), 7.61 (1H, d,J=9.1 Hz), 7.28 (1H, s), 7.24 (1H, d, J=9.2 Hz), 4.7 (1H, m), 4.36 (2H,s), 3.62 (2H, m), 3.31 (2H, m) 2.41 (3H, s), 2.22 (2H, m), 1.99 (2H, m).

Example 317

2-(4-((7-Fluoro-1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 29)

Selectfluor® (39.0 mg, 0.110 mmol) was added to a stirred mixture of2-(4-((1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(40 mg, 0.110 mmol, Example 167) in 1/1 DMF/MeCN (10 mL) at 0° C. Thereaction was then stirred at 100° C. under microwave irradiation for 1h. The mixture was concentrated and was residue was purified by reversephase HPLC (ACN/water with 0.1% TFA modifier) to provide the titlecompound. MS: 382 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ 8.07 (1H, s),7.83 (1H, s), 7.30-7.33 (2H, m), 4.48 (1H, m), 4.36 (2H, s), 3.65 (2H,br s), 3.22 (3H, t, J=10.1 Hz), 2.40 (3H, s), 2.12 (2H, m), 1.98 (2H,m).

Example 318

(R)-2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6-(3,3,3-trifluoro-2-hydroxypropyl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 30)

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(100 mg, 0.282 mmol, Example 1) in DMSO (5 mL) was added LHMDS (1 M,0.282 mL, 0.282 mmol). The reaction was stirred at RT B®re(R)-2-(trifluoromethyl)oxirane (31.6 mg, 0.282 mmol) was added. Afterstirring for 4 h, the crude mixture was direcly purified by reversephase HPLC (ACN/water with 0.1% NH₃OH modifier) to yield the titlecompound. MS: 467 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 7.87 (d, J=3.0 Hz,1H), 7.76 (s, 1H), 7.27 (m, 1H), 6.71 (d, J=9.0 Hz, 1H), 5.22 (s, 1H),4.46 (d, J=17 Hz, 1H), 4.39-4.37 (m, 1H), 4.27 (m, 1H), 4.00 (d, J=13.5Hz, 1H), 3.90 (s, 3H), 3.85 (m, 1H), 3.57 (m, 2H), 3.16 (m, 2H), 2.35(s, 3H), 2.10 (m, 2H), 1.94 (m, 2H).

The following examples in table 30 were prepared according to scheme 30using the procedure and conditions outlined in the synthesis of Example318.

TABLE 30 Example Structure Name MS (M + 1) 319

(S)-2-(4-((6- methoxypyridin- 3-yl)oxy) piperidin- 1-yl)-3-methyl-6-(3,3,3- trifluoro-2- hydroxypropyl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 467

Example 320

3-Methyl-2-(4-((6-(methylamino)pyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 31) Step 1: 6-(Methylamino)pyridin-3-ol

To a solution of 5-(benzyloxy)-N-methylpyridin-2-amine (60 mg, 0.280mmol, intermediate V) in MeOH (10 mL) was added Pd/C (10%, 29.8 mg,0.028 mmol). The reaction mixture was stirred at 10° C. for 1.5 h undera hydrogen atmosphere. The mixture was filtered, washing with MeOH (20mL) and the filtrate was evaporated under reduced pressure. The residuewas purified by prep-TLC (1/1 petroleum ether/EtOAc) to yield the titlecompound.

Step 2:3-Methyl-2-(4-((6-(methylamino)pyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of 6-(methylamino)pyridin-3-ol (20 mg, 0.161 mmol),2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(30 mg, 0.121 mmol, intermediate H1) and (E)-di-tert-butyldiazene-1,2-dicarboxylate (41.9 mg, 0.182 mmol) in toluene (2 mL) wasadded triphenylphosphine (47.7 mg, 0.182 mmol). The reaction mixture wasstirred at 80° C. for 15 h. The crude mixture was direcly purified byreverse phase HPLC (ACN/water with 0.1% TFA modifier) to yield the titlecompound. MS: 354 (M+1). ¹H NMR (400 MHz, methanol-d₄): δ 7.79 (1H, s),7.71 (1H, d, J=2.8 Hz), 7.30 (1H, dd, J=9.2, 2.8 Hz), 6.53 (1H, d, J=8.8Hz), 4.35-4.38 (1H, m), 4.33 (2H, s), 3.56-3.60 (2H, m), 3.17-3.20 (2H,m), 2.84 (3H, s), 2.38 (3H, s), 2.08-2.10 (2H, m), 1.87-1.90 (2H, m).

Example 321

2-(4-((2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 31) Step 1: 2,2-Dimethyl-2,3-dihydrobenzofuran-5-ol

To a solution of(2,2-dimethyl-2,3-dihydrobenzofuran-5-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane(60 mg, 0.219 mmol) in anhydrous MeOH (2 mL) was added H₂O₂ (35%, 0.192mL, 2.188 mmol) dropwise. The reaction was stirred at 30° C. for 16 hand was quenched with Na₂SO₃ and water (10 mL). The mixture wasextracted with EtOAc (3×10 mL) and the combined organic layers werewashed with brine, dried over anhydrous Na₂SO₄ and concentrated. Theresidue was purified by prep-TLC (3/1 petroleum ether/EtOAc) to give thetitle compound.

Step 2:2-(4-((2,2-Dimethyl-2,3-dihydrobenzofuran-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A solution of2-(4-hydroxypiperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(30 mg, 0.121 mmol, intermediate H1) in toluene (3 mL) was added2,2-dimethyl-2,3-dihydrobenzofuran-5-ol (29.9 mg, 0.182 mmol),triphenylphosphine (47.7 mg, 0.182 M®) and (E)-di-tert-butyldiazene-1,2-dicarboxylate (41.9 mg, 0.182 mmol). The mixture was stirredat 70° C. for 15 h under a nitrogen atmosphere. Then mixture wasconcentrated and was direcly purified by reverse phase HPLC (ACN/waterwith 0.1% NH₃OH modifier) to yield the title compound. MS: 394 (M+1). ¹HNMR (400 MHz, CDCl₃): δ 7.80 (1H, s), 6.80 (1H, s), 6.74 (1H, d, J=8.8Hz), 6.65 (1H, d, J=8.8 Hz), 5.98 (1H, s), 4.32-4.36 (3H, m), 3.50-3.56(2H, m), 3.12-3.17 (2H, m), 2.99 (2H, s), 2.36 (3H, s), 2.05-2.15 (2H,m), 1.82-1.90 (2H, m), 1.48 (6H, s).

The following examples in table 31 were prepared according to scheme 31using the procedure and conditions outlined in the synthesis of Example320 or 321 from prepared or commercially available starting materials.

TABLE 31 Example Structure Name MS (M + 1) 321A

2-(4-((1- (cyclopropyl- methyl)- 1H-pyrazol-4- yl)oxy) piperidin-1-yl)-3-methyl- 6,7-dihydro- 5H-pyrrolo[3,4-b] pyridin-5-one 368 321B

3-methyl-2-(4- ((1,2,4,5- tetrahydrobenzo [d]oxepin- 7-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b] pyridin- 5-one 394

Example 322

7-(2-Hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 32)

To a solution of2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(30 mg, 0.081 mmol, Example 18) in THF (5 mL) was added LDA (2 M, 0.081mL, 0.163 mmol) at −78° C. under an atmosphere of nitrogen. After 5 min,propan-2-one (5.20 mg, 0.090 mmol) was added to the reaction and themixture was allowed to warm to RT and was aged for 1 h. The mixture wasconcentrated and purified by reverse phase HPLC (ACN/water with 0.05%NH₃OH modifier) to yield the title compound. MS: 427 (M+1). ¹H NMR (400MHz, CDCl₃): δ 7.84 (1H, d, J=2.8 Hz), 7.77 (1H, s), 7.24 (1H, dd,J=8.4, 2.4 Hz), 6.68 (1H, d, J=8.4 Hz), 5.32 (1H, s), 4.30-4.40 (1H, m),4.15 (1H, s), 3.88 (3H, s), 3.42-3.60 (2H, m), 3.19 (3H, s), 3.06-3.18(2H, m), 2.33 (3H, s), 2.05-2.15 (2H, m), 1.86-2.02 (2H, m), 1.44 (3H,s), 0.83 (3H, s).

Examples 323A and 323B

(R)-7-(2-Hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-7-(2-hydroxypropan-2-yl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,6-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 32)

7-(Hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Example 322) from the procedure for Example 322 (vide supra) wasresolved by chiral SFC (AD column, 30% EtOH/CO₂) to afford isomer 323A(faster eluting): MS: 379 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ 7.83(1H, d, J=3.2 Hz), 7.73 (1H, s), 7.42 (1H, dd, J=8.8, 3.2 Hz), 6.75 (1H,d, J=8.8 Hz), 4.45-4.55 (1H, m), 4.29 (1H, s), 3.85 (3H, s), 3.48-3.63(2H, m), 3.07-3.33 (5H, m), 2.36 (3H, s), 2.07-2.17 (2H, m), 1.77-1.97(2H, m), 1.59 (3H, s), 0.81 (3H, s). Isomer 323B (slower eluting): MS:379 (M+1). ¹H NMR (500 MHz, methanol-d₄): δ 7.83 (1H, d, J=2.8 Hz), 7.73(1H, s), 7.42 (1H, dd, J=8.8, 2.8 Hz), 6.75 (1H, d, J=8.8 Hz), 4.45-4.55(1H, m), 4.29 (1H, s), 3.85 (3H, s), 3.48-3.63 (2H, m), 3.07-3.33 (5H,m), 2.36 (3H, s), 2.07-2.17 (2H, m), 1.77-1.97 (2H, m), 1.59 (3H, s),0.81 (3H, s).

Example 324

2-(4-((2-Hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 33) Step 1: Methyl6-(4-((2-(benzyloxy)-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (20.51 mg,0.097 mmol, intermediate A1) in N-methyl-2-pyrrolidinone (0.5 mL) wasadded 4-((2-(benzyloxy)-2,3-dihydro-1H-inden-5-yl)oxy)piperidine (21 mg,0.065 mmol) and DIPEA (0.034 mL, 0.195 mmol). The reaction was heated at80° C. for 15 h. The mixture was cooled to RT and partitioned with waterand EtOAc. The organic layer was dried over anhydrous sodium sulfate,filtered, and concentrated to yield the title compound, which was useddirectly without further purification. MS: 498 (M+1).

Step 2:2-(4-((2-(Benzyloxy)-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A mixture of methyl6-(4-((2-(benzyloxy)-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate(32 mg, 0.064 mmol) and Raney® nickel (5.51 mg, 0.064 mmol) in methanol(1 mL) was degassed and placed under a hydrogen atmosphere (45 psi). Themixture was stirred at 25° C. for 2 h. The mixture was filtered througha celite pad and the filtrate was concentrated to yield the titlecompound, which was used directly without further purification. MS: 470(M+1).

Step 3:2-(4-((2-Hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

A mixture of2-(4-((2-(benzyloxy)-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(25 mg, 0.053 mmol) and Pd/C (10%, 56.7 mg, 0.053 mmol) in methanol (10mL) was degassed and placed under a hydrogen atmosphere (45 psi). Themixture was stirred at 45° C. for 3 h. The mixture was cooled to RT,filtered and concentrated to dryness. The residue was purified byreverse phase HPLC (ACN/water with 0.1% NH₃OH modifier) to afford thetitle compound. MS: 380 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (1H, s),7.15 (1H, d, J=7.6 Hz), 6.86 (1H, s), 6.79 (1H, d, J=8.0 Hz), 6.28 (1H,br s), 4.70-4.75 (1H, m), 4.46-4.50 (1H, m), 4.36 (2H, s), 3.52-3.62(2H, m), 3.14-3.25 (4H, m), 2.88 (2H, td, J=10.8, 4.8 Hz), 2.36 (3H, s),2.10-2.25 (2H, m), 1.89-2.02 (2H, m).

Examples 324A and 324B

(S)-2-(4-((2-Hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-2-(4-((2-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 33)

2-(4-((2-Hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-onewas resolved by chiral SFC (OJ column, 40% EtOH with 0.1% NH₃modifer/CO₂) to afford isomer 324A (faster eluting, S-isomer): MS: 380(M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (1H, s), 7.14 (1H, d, J=8.0 Hz),6.86 (1H, s), 6.79 (1H, d, J=8.0 Hz), 6.26 (1H, br s), 4.72 (1H, br s),4.43-4.53 (1H, m), 4.36 (2H, s), 3.55-3.58 (2H, m), 3.12-3.22 (4H, m),2.81-2.94 (2H, m), 2.36 (3H, s), 2.07-2.18 (2H, m), 1.90-2.01 (2H, m).Isomer 324B (slower eluting, R-isomer): MS: 380 (M+1). ¹H NMR (400 MHz,CDCl₃): δ 7.80 (1H, s), 7.15 (1H, d, J=8.0 Hz), 6.86 (1H, s), 6.79 (1H,d, J=8.0 Hz), 4.72 (1H, br s), 4.49 (1H, br s), 4.36 (2H, s), 3.51-3.63(2H, m), 3.13-3.25 (4H, m), 2.81-2.94 (2H, m), 2.36 (3H, s), 2.12 (2H,s), 1.90-2.01 (2H, m).

Examples 324C and 324D

(S)-2-(4-((7-Hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-2-(4-((7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 33) Step 1: Methyl6-(4-((7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (34.8 mg,0.165 mmol) in DMF (5 mL) was added7-((tert-butyldimethylsilyl)oxy)-3-(piperidin-4-yloxy)-6,7-dihydro-5H-cyclopenta[b]pyridine(60 mg, 0.138 mmol) and TEA (0.058 mL, 0.413 mmol) at RT. The reactionwas then heated 80° C. for 2 h before cooling to RT and quenching withwater (50 mL). The mixture was extracted with EtOAc (3×30 mL) and thecombined organic layer were dried over anhydrous sodium sulfate,filtered and concentrated in vacuo. The residue was purified by silicagel chromatography (1:3 petroleun ether:THF) to give the title compound.

Step 2:2-(4-((7-((tert-Butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl6-(4-((7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate(40 mg, 0.077 mmol) in MeOH (10 mL) was added nickel (4.49 mg, 0.077mmol) and ammonium hydroxide (0.5 mL). The system was stirred under 50psi under an hydrogen atmosphere at 25° C. for 3 h. The mixture wasfiltered and the filtrate was concentrated in vacuo to provide the titlecopmound.

Step 3:(S)-2-(4-((7-Hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-2-(4-((7-hydroxy-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

In a solution of2-(4-((7-((tert-butyldimethylsilyl)oxy)-6,7-dihydro-5H-cyclopenta[b]pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(25 mg, 0.051 mmol) in THF (3 mL) was added TBAF (1 mL, 1.0 mmol) andstirred at RT for 1 h. The mixture was diluted with water (30 mL) andextracted with EtOAc (3×30 mL) and the combined organic layers werewashed with brine (30 mL), dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by prep-TLC (10% MeOH inDCM) to give racemic product which was resolved by chiral SFC (ADcolumn, 50% EtOH/CO₂) to afford isomer 324C (faster eluting): MS: 381(M+1). ¹H NMR (400 MHz, CDCl₃): δ 8.10 (s, 1H), 7.74 (s, 1H), 7.08 (s,1H), 5.90 (s, 1H), 5.05-5.19 (m, 1H), 4.46-4.48 (m, 1H), 4.29 (s, 2H),3.45-3.55 (m, 2H), 3.10-3.20 (m, 2H), 2.92-3.03 (m, 2H), 2.45-2.55 (m,2H), 2.29 (s, 3H), 2.14-1.85 (m, 4H). Isomer 324D (slower eluting): MS:381 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 8.09 (s, 1H), 7.74 (s, 1H), 7.08(s, 1H), 6.01 (s, 1H), 5.05-5.19 (m, 1H), 5.43-5.53 (m, 1H), 4.29 (s,2H), 3.45-3.55 (m, 2H), 3.10-3.20 (m, 2H), 2.92-3.03 (m, 2H), 2.45-2.55(m, 2H), 2.29 (s, 3H), 2.14-1.85 (m, 4H).

Example 324E

2-(4-((6-((2-Hydroxyethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 33) Step 1: Methyl6-(4-((6-((2-(benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate

To a solution of methyl 6-chloro-2-cyano-5-methylnicotinate (77 mg,0.367 mmol, intermediate A1) andN-(2-(benzyloxy)ethyl)-5-(piperidin-4-yloxy)pyridin-2-amine (80 mg,0.244 mmol, intermediate O) in DMF (5 mL) was added DIPEA (0.21 mL, 1.22mmol). The reaction mixture was stirred at 80° C. for 15 h. The solventwas evaporated under reduced pressure and purified by silica gelchromatography (0-50% EtOAc/petroleum ether) to give the title compound.MS: 502 (M+1).

Step 2:2-(4-((6-((2-(Benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl6-(4-((6-((2-(benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-2-cyano-5-methylnicotinate(100 mg, 0.199 mmol) in MeOH (15 mL) was added nickel (5.85 mg, 0.10mmol). The reaction was stirred at 15° C. for 3 h under an atmosphere ofhydrogen (50 psi). The mixture was filtered and solvent was evaporatedunder reduced pressure to give the title compound, which was used tonext step without further purification. MS: 474 (M+1).

Step 3:2-(4-((6-((2-Hydroxyethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((6-((2-(benzyloxy)ethyl)amino)pyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(90 mg, 0.190 mmol) in MeOH (15 mL) was added Pd/C (20.2 mg, 0.019 mmol,10%). The reaction was stirred at 15° C. for 15 h under an atmosphere ofhydrogen (30 psi). The mixture wacaniltered and concentrated beforebeing purified by reverse phase HPLC (ACN/water with 0.1% TFA modifier)to yield the title compound. MS: 384 (M+1). ¹H NMR (400 MHz,methanol-d₄): δ 7.74-7.83 (2H, m), 7.56 (1H, s), 7.10 (1H, d, J=9.78Hz), 4.47-4.59 (1H, m), 4.33 (s, 2H), 3.80 (2H, t, J=4.89 Hz), 3.52-3.62(2H, m), 3.49 (2H, t, J=4.89 Hz), 3.19-3.23 (2H, m), 2.38 (3H, s),2.10-2.22 (2H, m), 1.85-1.99 (2H, m).

Example 325

Ammonium(2-(4-(3-cyanophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phosphonate(Scheme 34) Step 1: Diethyl(2-(4-(3-cyanophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phosphonate

To a solution of3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile(0.348 g, 4.02 mmol, Example 3) and diethyl phosphorochloridate (173 mg,4.82 mmol) in THF (10 mL) was added NaH (60%, 24 mg, 4.82 mmol) at RT.The reaction was stirred at RT under an atmosphere of nitrogen for 15 hbefore quenching with saturated, aqueous ammonium chloride (10 mL) andpartitioning with EtOAc (50 mL×3). The combined organic layers weredried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by silica gel chromatography (10:1 to 2:3 petroleumether:EtOAc) to yield the title compound. MS: 485 (M+1).

Step 2: Ammonium(2-(4-(3-cyanophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5,7-dihydro-6H-pyrrolo[3,4-b]pyridin-6-yl)phosphonate

To a solution of diethyl(2-(4-(3-cyanophenoxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)phosphonate(300 mg, 0.619 mmol) in dry MeCN (5 mL) was added TMS-Br (0.402 mL, 3.10mmol). The reaction was stirred at 60° C. for 2 h under a nitrogenatmosphere. The volatiles were removed in vacuo and the residue wastreated with MeCN (5 mL) and Et₃N (0.25 mL) and then concentrated again.The residue was purified by reverse phase HPLC (ACN/water with 0.05%NH₃OH modifier) to afford the title compound. MS: 429 (M+1). ¹H NMR (400MHz, CDCl₃): δ 7.77 (1H, s), 7.46 (1H, t, J=8.0), 7.35 (1H, s),7.27-7.32 (2H, m), 4.69-4.75 (1H, m), 4.57 (2H, s), 3.56-3.65 (2H, m),3.22-3.27 (2H, m), 2.37 (3H, s), 2.10-2.19 (2H, m), 1.85-1.95 (2H, m).

Example 326

2-(4-((6-Hydroxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 35)

To2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(50 mg, 0.141 mmol, Example 1) in chloroform (564 μL) was addediodotrimethylsilane (60.2 μL, 0.423 mmol) dropwise at RT. The reactionwas heated to 70° C. for 3 h and was then cooled to RT before thevolatiles were removed under reduced pressure. The residue was purifiedby mass-directed reverse phase HPLC (ACN/water with 0.1% NH₃OH modifier)to afford the title compound. MS: 341 (M+1). ¹H NMR (500 MHz, DMSO-d₆):δ 8.33 (1H, s), 7.72 (1H, s), 7.47 (1H, d, J=9.64 Hz), 7.34 (1H, s),6.47 (1H, d, J=9.59 Hz), 4.32 (1H, m), 4.24 (2H, s), 3.47 (2H, br s),3.05 (2H, t, J=10.86 Hz), 2.30 (3H, s), 2.02 (2H, br s), 1.73 (2H, d,J=11.08 Hz).

Example 327

3-Chloro-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 36) Step 1: Methyl2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate

To a solution of 2-methoxy-5-(piperidin-4-yloxy)pyridine hydrochloride(1.55 g, 6.35 mmol, intermediate F1) in DMF (8 mL) was added methyl2,6-difluoronicotinate (1.0 g, 5.78 mmol) at RT. The mixture was cooledto 0° C., before N-ethyl-N-isopropylpropan-2-amine (2.24 g, 17.3 mmol)was added. The reaction mixture was allowed to warm to RT and wasstirred 18 h before diluting with EtOAc (30 mL) and water (30 mL). Theaqueous layer was extracted with EtOAc (30 mL×3) and the combined theorganic layers were washed with brine (30 mL×4), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and purifiedby silica gel column chromatography (2/1 petroleum ether/EtOAc) to yieldthe title compound. MS: 362 (M+1).

Step 2: Methyl5-chloro-2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate

In a 20 mL schlenk tube was prepared a stirred solution of methyl2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate (200mg, 0.553 mmol) in CHCl₃ (4 mL). 1-Chloropyrrolidine-2,5-dione (81 mg,0.609 mmol) was added and the reaction mixture was stirred for 4 h at80° C. The reaction was cooled and concentrated in vacuo and residue waspurified by silica gel column chromatography (3/1 petroleum ether/EtOAc)to give the title compound. MS: 396 (M+1).

Step 3:5-Chloro-2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinicAcid

To a solution of methyl5-chloro-2-fluoro-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate(240 mg, 0.606 mmol) in DMSO (5 mL) was added sodium cyanide (44.6 mg,0.910 mmol). The mixture was stirred at 80° C. for 16 h. After coolingto RT, the mixture was diluted with EtOAc (30 mL) and water (30 mL). Theaqueous layer was extracted with EtOAc (30 mL×3) and the combined theorganic layers were washed with brine (30 mL×4), dried over anhydroussodium sulfate and filtered. The filtrate was concentrated and was usedto the next step without further purification. MS: 389 (M+1).

Step 4: Methyl5-chloro-2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate

To a solution of5-chloro-2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinicacid (100 mg, 0.257 mmol) in DMF (5 mL) was added potassium carbonate(71.1 mg, 0.514 mmol) and iodomethane (43.8 mg, 0.309 mmol). The mixturewas stirred for 3H at Rt. Before diluting with EtOAc (30 mL) and water(30 mL). The aqueous layer was extracted with EtOAc (30 mL×3) and thecombined the organic layers were washed with brine (30 mL×4), dried overanhydrous magnesium sulfate and filtered. The filtrate concentrated wasused without further purification. MS: 403 (M+1).

Step 5:3-Chloro-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl5-chloro-2-cyano-6-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)nicotinate(50 mg, 0.099 mmol) in MeOH (20 mL) was added molybdenum promoted nickel(skeletal) (15.36 mg, 0.099 mmol). The suspension was degassed andpurged with hydrogen several times. The mixture was stirred at 20° C.for 3 h under an atmosphere of hydrogen (50 psi). After placing thesystem under an atmosphere of nitrogen, the suspension was filtered andthe filtrate was concentrated, the residue was purified HPLC (ACN/waterwith 0.1% NH₃OH modifier) to provide the title compound. MS: 375 (M+1).¹H NMR (400 MHz, methanol-d₄): δ 7.95 (1H, s), 7.82 (1H, d, J=2.8 Hz),7.42 (1H, dd, J=8.8, 2.8 Hz), 6.74 (1H, d, J=9.2 Hz), 4.49-4.53 (1H, m),4.34 (2H, s), 3.84 (3H, s), 3.75-3.82 (2H, m), 3.34-3.42 (2H, m),2.02-2.15 (2H, m), 1.78-1.94 (2H, m).

Example 328

2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 37) Step 1: Dimethyl2-cyano-6-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-5-methylpyridine-3,4-dicarboxylate

To a solution of dimethyl6-chloro-2-cyano-5-methylpyridine-3,4-dicarboxylate (2.8 g, 10.4 mmol)in DMF (20 mL) was added4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidine hydrochloride (4.0 g,15.6 mmol) and triethylamine (3.16 g, 31.3 mmol) under an atmosphere ofnitrogen. The reaction was heated to 80° C. with stirring for 2 h beforethe mixture was cooled to RT and quenched with water (50 mL). Afterextracting with EtOAc (30 mL×3), the combined organic layers were driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo. The residue was purified by silica gelchromatography (3:1 petroleum ether:EtOAc) to provide the titlecompound. MS: 452 (M+1).

Step 2: Methyl2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-4-carboxylate

To a solution of dimethyl2-cyano-6-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-5-methylpyridine-3,4-dicarboxylate(4.4 g, 8.77 mmol) in MeOH (100 mL) and THF (5 mL) was added Raney®nickel (0.515 g, 8.77 mmol) and ammonium hydroxide (5 mL). The reactionwas stirred at 30° C. for 3 h under 50 psi of hydrogen. The mixture wasfiltered and the filtrate was concentrated in vacuo to afford the titlecompound. MS: 424 (M+1).

Step 3:2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-4-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-4-carboxylate(4.0 g, 9.45 mmol) in THF (50 mL) was added LiBH₄ (0.617 g, 28.3 mmol)at 30° C. for 16 h. The reaction mixture was quenched with water (100mL) and extracted with EtOAc (100 mL×3), the organic layers were driedover anhydrous sodium sulfate, filtered and the filtrate wasconcentrated in vacuo to give the title compound. MS: 396 (M+1).

Step 4:2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-4-(hydroxymethyl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(4.0 g, 10.12 mmol) in AcOH (70 mL) was added zinc (1.98 g, 30.3 mmol)at 100° C. for 16 h. The reaction mixture was filtered and the filtratewas concentrated in vacuo. The material was dissolved in 10% MeOH in DCMto load onto a column for purification by silica gel chromatography(5-35% 3:1 EtOAc:EtOH in hexanes with 1% NH₄OH modifer) to afford thetitle compound. MS: 380 (M+1). ¹H NMR (300 MHz, DMSO-d₆): δ 8.29 (1H,s), 6.17-6.19 (1H, m), 6.87-6.94 (2H, m), 4.91-4.93 (4H, m), 4.54 (1H,s), 4.15 (2H, s), 3.30-3.38 (2H, m), 2.98-3.04 (2H, m), 2.47-2.49 (3H,m), 2.16 (3H, s), 2.03-2.07 (2H, m), 1.72-1.78 (2H, m),

Examples 329A and 329B

(R)-2-(4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 37) Step 1: Methyl2-cyano-6-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methylnicotinate

4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidine (205 mg, 1.0mmol) and methyl 6-chloro-2-cyano-4-methylnicotinate (211 mg, 1.0 mmol)were added to a flask and was dissolved in NMP (3 mL). DIPEA (0.524 mL,3.0 mmol) was then added and the system was sealed and heated to 80° C.for 2 h. After cooling to RT, the reaction was partitioned between waterand ethyl acetate. The organic layer was washed twice more with waterand then with brine, dried over anhydrous sodium sulfate, filtered andconcentrated. The residue was purified on a silica gel column elutingwith 10-50% EtOAc in hexanes to afford the title product. MS: 380 (M+1).

Step 2:2-(4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

Methyl2-cyano-6-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methylnicotinate(303 mg, 0.80 mmol) was dissolved in 2,2,2-trifluoroethanol (4 mL) andAcOH (0.14 mL, 2.4 mmol). The system was evacuated and charged withnitrogen before 10% Pd/C (85 mg, 0.08 mmol) was added. The system wasevacuated and charged with hydrogen and was stirred for 3 h. Thereaction was placed under nitrogen and then filtered (celite) and thefiltrate was concentrated. Toluene was used to azeotrope remaining AcOHbefore the residue was dissolved in MeOH (4 mL) and TEA (0.83 mL, 6.0mmol). After stirring the mixture at RT for 15 h, the reaction wasconcentrated and the residue was purified by silica gel chromatography(0-30% 3:1 EtOAc:EtOH in DCM) to provide the title compound. MS: 352(M+1).

Step 3:3-Bromo-2-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

2-(4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(269 mg, 0.766 mmol) was suspended in 5 mL DCE. NBS (150 mg, 0.842 mmol)was added and the reaction was stirred for 15 h at RT. The material wasdirectly purified by silica gel chromatography (10-50% 3:1 EtOAc:EtOH inhexanes) to give the title compound. M®430, 432 (M+1).

Step 4:(R)-2-(4-((2,2-Difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

3-Bromo-2-(4-((2,2-difluoro-1-methylcyclopropyl)methoxy)piperidin-1-yl)-4-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(100 mg, 0.232 mmol) was suspended in 1,4-dioxane (2 mL). The additionof methylzinc chloride (2 M in THF, 0.58 mL, 1.16 mmol) was followed byPd(Ph₃P)₄ (13.4 mg, 0.012 mmol). The system was sealed and then heatedto 80° C. with stirring for 3 h. The reaction was then cooled in an icebath and quenched by the dropwise addition of MeOH (1 mL). The volatileswere removed and the residue was directly purified by silica gelchromatography (20% 3:1 EtOAc:EtOH in hexanes) to afford the racemate.Resolution was carried out by chiral SFC (Lux-Amylose-1 AD-H, 15%MeOH/CO₂) to afford isomer 329A (faster eluting): MS: 366 (M+1). ¹H NMR(500 MHz, CDCl₃): δ 5.91 (br s, 1H), 4.34 (br s, 2H), 3.50 (m, 5H), 3.02(br s, 2H), 2.64 (s, 3H), 2.23 (s, 3H), 2.03 (br s, 2H), 1.77 (br s,2H), 1.26 (s, 3H), 1.18 (m, 1H), 1.08 (m, 1H). Isomer 324D (slowereluting): MS: 366 (M+1). ¹H NMR (500 MHz, CDCl₃): δ 5.91 (br s, 1H),4.34 (br s, 2H), 3.50 (m, 5H), 3.02 (br s, 2H), 2.64 (s, 3H), 2.23 (s,3H), 2.03 (br s, 2H), 1.77 (br s, 2H), 1.26 (s, 3H), 1.18 (m, 1H), 1.08(m, 1H).

The following examples in table 37 were prepared according to scheme 37using the procedure and conditions outlined in the synthesis of Examples328, 329A and 329B, from prepared or known starting materials.

TABLE 37 Example Structure Name MS (M + 1) 330

2-(4- (cyclobutylmethoxy) piperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 330 331

3,4-dimethyl- 2-(4-((1- methyl-1H- pyrazol-4-yl) oxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 342 332

2-(4-(isochroman-7- yloxy)piperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H-pyrrolo[3,4-b] pyridin- 5-one 394 333

2-(4-((2,3- dihydrobenzofuran- 6-yl)oxy)piperidin- 1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 380 334A 334B

(R)-2-(4-((2- hydroxy-2,3- dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-3,4-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4-b] pyridin-5-one and(S)-2-(4-((2- hydroxy-2,3- dihydro-1H- inden-5-yl) oxy)piperidin-1-yl)-3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 394 394 335A335B

(R)-2-(4-((2- methoxy-2,3- dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-3,4-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4-b] pyridin-5-one and(S)-2-(4-((2- methoxy-2,3- dihydro-1H-inden- 5-yl)oxy)piperidin-1-yl)-3,4-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 408 408336

2-(4-(isochroman- 6-yloxy) piperidin-1-yl)- 3,4-dimethyl-6,7-dihydro-5H- pyrrolo[3,4-b] pyridin- 5-one 394 226A

2-((3R,4R)-3- fluoro-4- ((6-methoxypyridin- 3-yl)oxy)piperidin-1-yl)-3,4-dimethyl- 6,7-dihydro-5H- pyrrolo[3,4-b] pyridin-5-one 387336B 336C

(R)-2-(3,3- difluoro-4-((1- methyl-1H-pyrazol- 4-yl)oxy)piperidin-1-yl)-3,4- dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b] pyridin-5-one and(S)-2-(3,3- difluoro-4- ((1-methyl- 1H-pyrazol-4-yl)oxy)piperidin-1-yl)- 3,4-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin-5-one 378 378

Examples 337A and 337B

(S)-2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(337A) and(R)-2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(337B) (Scheme 38) Step 1:2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(208 mg, 0.548 mmol) in degassed DMSO (3.0 mL) was cooled in ice bathunder an atmosphere of nitrogen. LHMDS (1.5 M in THF, 400 μL, 0.60 mmol)was added dropwise and the reaction was allowed to warm to ambienttemperature followed by methyl iodide (39 μl, 0.62 mmol). After 2 h atRT, the reaction was quenched with saturated aqueous ammonium chlorideand partitioned with EtOAc. The organic layer was washed with water,brine, dried (anhydrous sodium sulfate) and concentrated. The materialwas purified by silica gel chromatography (5-30% 3:1 EtOAc:EtOH with 1%NH₄OH modifer in hexanes) to yield the title compound. MS: 394 (M+1).

Step 2:(S)-2-(4-((1,3-Dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(122 mg, 0.31 mmol) in THF (3 mL) was added LDA (2 M in THF, 0.47 mL,0.93 mmol) at −78° C. under an atmosphere of nitrogen. After 15 min, aslurry of 1H-benzo[d][1,2,3]triazol-1-yl)methanol (92 mg, 0.62 mmol) inTHF (0.5 mL) was added to the reaction at −78° C. and the reaction wasaged for 1 h at this temperature. The reaction was quenched withsaturated aqueous ammonium chloride and extracted with EtOAc (2×). Thecombined organic extracts were washed with water (2×), brine, dried(anhydrous sodium sulfate), filtered, and concentrated. The material waspurified by silica gel chromatography (10-40% 3:1 EtOAc:EtOH with 1%NH₄OH modifer in hexanes) to yield the racemate. The title compoundswere resolved by chiral SFC (AD-H column, 40% isopropanol/CO₂) to affordisomer 337A (faster eluting, S-isomer): MS: 424 (M+1). ¹H NMR (400 MHz,CDCl₃): δ 7.15 (1H, d, J=8.0 Hz), 6.82-6.89 (2H, m), 5.06-5.09 (4H, m),4.20-4.27 (2H, m), 3.62-3.65 (2H, m), 3.48 (2H, br s), 3.11 (5H, br s),2.64 (3H, s), 2.23 (3H, s), 2.14 (2H, m), 1.99 (2H, m). Isomer 337B(slower eluting, R-isomer): MS: 424 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.86 (1H, s), 7.71 (1H, s), 6.71 (1H, d, J=9.02 Hz), 4.38 (1H, s), 4.32(1H, s), 4.19 (2H, br s), 3.90 (3H, d, J=2.29 Hz), 3.80 (1H, t, J=9.41Hz), 3.53 (4H, br s), 3.14 (4H, br s), 2.31 (3H, s), 2.11 (2H, br s),1.94 (2H, br s).

Examples 337C and 337D

(S)-7-(hydroxymethyl)-2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(337C) and(R)-7-(hydroxymethyl)-2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(337D) (Scheme 38) Step 1 Step 2:(S)-7-(hydroxymethyl)-2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(R)-7-(hydroxymethyl)-2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(1.12 g, 2.75 mmol) in THF (20 mL) was added lithiumbis(trimethylsilyl)amide (1 M, 8.25 mL, 8.25 mmol) dropwise at −70° C.under an inert nitrogen atmosphere. After aging for 30 min, a slurry of(1H-benzo[d][1,2,3]triazol-1-yl)methanol (0.574 g, 3.85 mmol) in THF (5mL) was added dropwise and the reaction mixture was stirred at −70° C.for 30 min. The reaction was quenched by the addition of aqueous NH₄Cl(saturated, 15 mL) and was subsequently treated with water (25 mL) andextracted with EtOAc (25 mL×3). The combined organic layers were driedover anhydrous sodium sulfate, filtered and concentrated. The materialwas purified by silica gel chromatography (1:1 THF:petroleum ether) toyield the racemate. The title compounds were resolved by chiral SFC (ADcolumn, 40% EtOH with 0.05% diethylamine modifier/CO₂) to afford isomer337C (faster eluting, S-isomer): MS: 438 (M+1). ¹H NMR (400 MHz, MeOD):δ 7.03 (1H, d, J=8.4 Hz), 6.79 (1H, dd, J=8.4, 2.4 Hz), 6.64 (1H, d,J=2.4 Hz), 4.70 (2H, s), 4.50-4.52 (1H, m), 4.25-4.27 (1H, m), 4.08-4.18(2H, m), 3.93 (2H, t, J=5.6 Hz), 3.49-3.52 (2H, m), 3.05-3.17 (5H, m),2.76 (2H, t, J=5.6 Hz), 2.59 (3H, s), 2.25 (3H, s), 2.05-2.14 (2H, m),1.78-1.95 (2H, m). Isomer 337D (slower eluting, R-isomer): MS: 438(M+1). ¹H NMR (400 MHz, MeOD): δ 7.01 (1H, d, J=8.8 Hz), 6.76 (1H, d,J=8.4, 2.4 Hz), 6.61 (1H, d, J=2.4 Hz), 4.68 (2H, s), 4.49-4.52 (1H, m),4.24-4.27 (1H, m), 4.06-4.16 (2H, m), 3.91 (2H, t, J=5.6 Hz), 3.41-3.50(2H, m), 3.05-3.15 (5H, m), 2.74 (2H, t, J=5.6 Hz), 2.56 (3H, s), 2.23(3H, s), 2.04-2.12 (2H, m), 1.76-1.92 (2H, m). The following examples intable 38 were prepared according to scheme 38 using the procedure andconditions outlined in the synthesis of Examples 337A, 337B, 337C and337D from prepared or commercially available starting materials.

TABLE 38 Example Structure Name MS (M +1) 338

3,6-dimethyl-2-(4-((1- methylcyclopropyl) methoxy)piperidin-1-yl)-6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 330 339

(S)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one360 340

(R)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one360 341

(S)-3-ethyl-7- (hydroxymethyl)-6- methyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one374 341A

(S)-2-((3S,4R)-3- fluoro-4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)-7- (hydroxymethyl)-3,4,6- trimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 392 342

(R)-3-ethyl-7- (hydroxymethyl)-6- methyl-2-(4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one374 342A

(R)-2-((3S,4R)-3- fluoro-4-((1- methylcyclopropyl)methoxy)piperidin-1-yl)-7- (hydroxymethyl)-3,4,6- trimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 392 343

(S)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((5- methylpyridin-3-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 383343A

(S)-7-(hydroxymethyl)- 2-(4-((6- methoxypyridin-3-yl)oxy)piperidin-1-yl)- 3,4,6-trimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 413 344

(R)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((5- methylpyridin-3-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 383344A

(R)-7-(hydroxymethyl)- 2-(4-((6- methoxypyridin-3-yl)oxy)piperidin-1-yl)- 3,4,6-trimethyl-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 5-one 413 345

(S)-3-((1-(7- (hydroxymethyl)-3,6- dimethyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 393 346

(R)-3-((1-(7- (hydroxymethyl)-3,6- dimethyl-5-oxo-6,7- dihydro-5H-pyrrolo[3,4-b]pyridin- 2-yl)piperidin-4- yl)oxy)benzonitrile 393 347

(S)-2-(4-(3,4- difluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,6-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 404 348

(R)-2-(4-(3,4- difluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,6-dimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 404 349

(S)-7-(hydroxymethyl)- 2-(4-(isochroman-7- yloxy)piperidin-1-yl)-3,6-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424 349A

(S)-7- (hydroxymethyl)-2-(4- (isochroman-6- yloxy)piperidin-1-yl)-3,6-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424 350

(R)-7-(hydroxymethyl)- 2-(4-(isochroman-7- yloxy)piperidin-1-yl)-3,6-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]yridin- 5-one 424 350A

(R)-7-(hydroxymethyl)- 2-(4-(isochroman-6- yloxy)piperidin-1-yl)-3,6-dimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424 351

(S)-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-3-ethyl-7- (hydroxymethyl)-6- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 424 351A

(S)-2-(4-((1,3- dihydroisobenzofuran- 5-yl)oxy)piperidin-1-yl)-6-ethyl-7- (hydroxymethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 438 352

can-2-(4-((1,3-dihydro- 2-benzofuran-5- yl)oxy)piperidin-1-yl)-3-ethyl-7- (hydroxymethyl)-6- methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 424 352A

(R)-2-(4-((1,3- dihydroisobenzofuran- 5-yl)oxy)piperidin-1-yl)-6-ethyl-7- (hydroxymethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 438 353

(S)-2-(4-(4- fluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 400 354

(R)-2-(4-(4- fluorophenoxy) piperidin-1-yl)-7- (hydroxymethyl)-3,4,6-trimethyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one 400 355

(S)-2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 356

(R)-2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)-7-(hydroxymethyl)-3,6- dimethyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 410 357

(S)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 372358

(R)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 372359

(S)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 422360

(R)-7-(hydroxymethyl)- 3,6-dimethyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 422361

(S)-3-ethyl-7- (hydroxymethyl)-2-(4- (isochroman-7-yloxy)piperidin-1-yl)- 6-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 438 362

(R)-3-ethyl-7- (hydroxymethyl)-2-(4- (isochroman-7-yloxy)piperidin-1-yl)- 6-methyl-6,7-dihydro- 5H-pyrrolo[3,4-b]pyridin-5-one 438 363

(S)-3-ethyl-7- (hydroxymethyl)-6- methyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 436364

(R)-3-ethyl-7- (hydroxymethyl)-6- methyl-2-(4-((1- methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)- 6,7-dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 424365

(S)-2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)- 3-ethyl-7-(hydroxymethyl)-6- methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one424 366

(R)-2-(4-((2,3- dihydrobenzofuran-6- yl)oxy)piperidin-1-yl)- 3-ethyl-7-(hydroxymethyl)-6- methyl-6,7-dihydro- 5H-pyrrolo[3,4- b]pyridin-5-one436 367

(S)-2-(4-((1,3- dihydroisobenzofuran- 5-yl)oxy)piperidin-1-yl)-6-ethyl-7- (hydroxymethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 438 368

(R)-2-(4-((1,3- dihydroisobenzofuran- 5-yl)oxy)piperidin-1-yl)-6-ethyl-7- (hydroxymethyl)-3,4- dimethyl-6,7-dihydro-5H-pyrrolo[3,4- b]pyridin-5-one 438 369

(S)-7-(hydroxymethyl)- 2-(4-(isochroman-6- yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438 370

(R)-7-(hydroxymethyl)- 2-(4-(isochroman-6- yloxy)piperidin-1-yl)-3,4,6-trimethyl-6,7- dihydro-5H- pyrrolo[3,4-b]pyridin- 5-one 438

Example 371

2-(4-((1-(2-Hydroxyethyl)-1H-indazol-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 39)

To a solution of methyl2-(5-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)-1H-indazol-1-yl)acetate(100 mg, 0.230 mmol) in THF (10 mL) was added LiBH₄ (10.0 mg, 0.459mmol). The reaction mixture was stirred 16 h at 25° C. before beingquenched with MeOH (5 mL). After stirring for 30 min at RT the volatileswere removed under reduced pressure and the residue was partitioned withsaturated aqueous NaHCO₃ (10 mL) and extracted with DCM (20 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overanhydrcan sodium sulfate, filtered and concentrated. The residue waspurified by HPLC (CAN/water with 0.1% TFA modifier) to provide the titlecompound. MS: 408 (M+1). ¹H NMR (400 MHz, MeOD): δ 7.90 (1H, s), 7.78(1H, s), 7.51 (1H, d, J=8.8 Hz), 7.25 (1H, s), 7.10-7.14 (1H, m),4.28-4.54 (1H, m) 4.44 (d, 2H, J=5.2 Hz), 4.32 (2H, s), 3.93 (2H, br s),3.55-3.61 (2H, m), 3.18-3.23 (2H, m), 2.37 (3H, s), 2.14-2.15 (2H, m),1.91-1.96 (2H, m).

Example 372

2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-4-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 40) Step 1:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-4-carbaldehyde

To a solution of4-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(80 mg, 0.208 mmol) in DCM (3 mL) was added DMP (177 mg, 0.416 mmol)under an atmosphere of nitrogen. The reaction mixture was stirred at 0°C. for 2 h. The reaction mixture was diluted with water (50 mL) andextracted with EtOAc (30 mL×3). The combined organic layers were washedwith brine (10 mL), dried over anhydrous sodium sulfate, filtered andconcentrated in vacuo to yield the title compound. MS: 383 (M+1).

Step 2:2-(4-((6-Methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-4-vinyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyltriphenylphosphonium bromide (42.0 mg, 0.118mmol) in THF (2 mL) was added LiHMDS (1 M in THF, 0.157 mL, 0.157 mmol)dropwise at −60° C. the reaction mixture was stirred at this temperaturefor 30 min and then2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridine-4-carbaldehyde(30 mg, 0.078 mmol) in THF (1 mL) was added dropwise at −60° C. Thereaction mixture was cooled to RT and was stirred for 12 h beforediluting with water (50 mL) and extracting with EtOAc (30 mL×3). Thecombined organic layers were washed with brine (10 mL), dried overanhydrous sodiucanulfate, filtered and concentrated in vacuo. Theresidue was purified by HPLC (CAN/water with 0.1% TFA modifier) toafford the title compound. MS: 381 (M+1). ¹H NMR (400 MHz, CDCl₃): δ7.87 (1H, d, J=3.2 Hz), 7.25-7.28 (1H, m), 6.68-6.72 (2H, m), 5.82 (1H,d, J=11.6 Hz), 5.71 (d, 1H, J=18.0 Hz), 4.35-4.37 (1H, m), 4.32 (2H, s),3.88 (3H, s), 3.50-3.60 (2H, m), 3.10-3.20 (2H, m), 2.35 (3H, s),2.09-2.11 (2H, m), 1.90-1.95 (2H, m).

Example 373

3-Methyl-2-(4-((2-oxo-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 41)

To a solution of2-(4-((2-hydroxy-2,3-dihydro-1H-inden-5-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(15 mg, 0.040 mmol) in DCM (1 mL) was added DMP (25.1 mg, 0.059 mmol).The mixture was stirred at 15° C. for 10 h and was thencanitered andconcentrated to give a residue. The material was purified by HPLC(MeCN/water with 0.1% TFA modifier) to afford the title compound. MS:378 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.80 (1H, s), 7.22 (1H, d, J=7.6Hz), 6.70-6.92 (2H, m), 6.77 (1H, br s), 4.53 (1H, br s), 4.38 (2H, s),3.50-3.57 (6H, m), 3.17-3.25 (2H, m), 2.36 (3H, s), 2.14 (2H, br s),1.99 (2H, br s).

Example 374A and 374B

(R)-2-(3,3-Difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(3,3-Difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 42) Step 1: Methyl2-cyano-6-(3,3-difluoro-4-((2-methylallyl)oxy)piperidin-1-yl)-5-ethylnicotinate

To a solution of methyl2-cyano-6-(3,3-difluoro-4-hydroxypiperidin-1-yl)-5-ethylnicotinate (250mg, 0.768 mmol) in dry DMF (5 mL) was added NaH (36.9 mg, 0.922 mmol) at0° C. After 30 min, a solution of 3-bromo-2-methylprop-1-ene (124 mg,0.922 mmol) in DMF (1 mL) was added dropwise to the reaction the systemwas allowed to warm to RT. After stirring for 6 h, the reaction wastreated with saturated aqueous ammonium chloride (1 mL) and water (20mL). The mixture was extracted with EtOAc (20 mL×3) and the combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated. The residue dissolved in a solution of MeOH (5 mL) andTMSCHN₂ (1 M in diethyl ether, 1 mL). After 30 min, the reaction wasquenched with AcOH and the volatiles were removed under reducedpressure. Purification by silica gel chromatography (0-30%EtOAc/petroleum ether) provided the title compound. MS: 380 (M+1).

Step 2: Methyl2-cyano-6-(3,3-difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-ethylnicotinate

To a solution of diiodomethane (1.06 g, 3.95 mmol) in DCM (5 mL) wasadded diethylzinc (1.1 M, 2.40 mL, 2.64 mmol) dropwise at 0° C. underand inert atmosphere. After 30 min, a solution of methyl2-cyano-6-(3,3-difluoro-4-((2-methylallyl)oxy)piperidin-1-yl)-5-ethylnicotinate(250 mg, 0.659 mmol) in dry DCM (1 mL) was added dropwise and thereaction was allowed to warm to 15° C. After 42 h, the reaction wastreated with saturated aqueous ammonium chloride (1 mL) and water (10mL). The mixture was extracted with DCM (20 mL×3) and the combinedorganic layers were dried over anhydrous sodium sulfate, filtered andconcentrated. Purification by silica gel chromatography (0-30%EtOAc/petroleum ether) afforded the title compound. MS: 394 (M+1).

Step 3:(R)-2-(3,3-Difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-oneand(S)-2-(3,3-Difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-3-ethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-cyano-6-(3,3-difluoro-4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-5-ethylnicotinate(160 mg, 0.407 mmol) in MeOH (2 mL) was added nickel (23.9 mg, 0.407mmol) and 2 drops of concentrated NH₃. The mixture was stirred at 20° C.for 3 h under a hydrogen atmosphere (50 psi). The mixture was filteredand the filtrate was concentrated to give the racemate. The titlecompounds were resolved by chiral SFC (AD-H column, 25% MeOH with 0.1%NH₄OH modifier/CO₂) to afford isomer 374A (faster eluting isomer): MS:366 (M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.94 (1H, s), 6.07 (1H, br s),4.38 (2H, s), 3.59-3.71 (2H, m), 3.54 (1H, d, J=9.6 Hz), 3.25-3.40 (3H,m), 3.17-3.20 (1H, m), 2.71 (2H, q, J=7.2 Hz), 2.12-2.14 (1H, m),2.02-2.04 (1H, m), 1.30 (3H, t, J=7.6 Hz), 1.16 (3H, s), 0.43-0.45 (2H,m), 0.32-0.35 (2H, m). Isomer 374B (slower eluting isomer): MS: 366(M+1). ¹H NMR (400 MHz, CDCl₃): δ 7.94 (1H, s), 6.14 (1H, brs), 4.38(2H, s), 3.59-3.71 (2H, m), 3.54 (1H, d, J=9.6 Hz), 3.25-3.40 (3H, m),3.17-3.20 (1H, m), 2.71 (2H, q, J=7.2 Hz), 2.12-2.14 (1H, m), 2.02-2.04(1H, m), 1.30 (3H, t, J=7.6 Hz), 1.16 (3H, s), 0.43-0.45 (2H, m),0.32-0.35 (2H, m).

Example 375

6-(2-Hydroxyethyl)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one(Scheme 43) Step 1: Methyl2-(7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate

To a solution of methyl2-(2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate(40 mg, 0.094 mmol) in THF (2 mL) was added lithiumbis(trimethylsilyl)amide (47.1 mg, 0.281 mmol) dropwise at −70° C. Afterstirring for 15 min, a solution of(1H-benzo[d][1,2,3]triazol-1-yl)methanol (21.0 mg, 0.141 mmol) in THF(0.5 mL) was added dropwise and then stirred for 30 min at −70° C. Thereaction was quenched with saturated aqueous NH₄Cl (0.5 mL), treatedwith water (10 mL) and the mixture was extracted with EtOAc (20 mL×3).The combined organic layers were dried over anhydrous sodium sulfate,filtered and concentrated. The residue was purified by prep-TLC (100%EtOAc) to give the title compound. MS: 457 (M+1).

Step 2:6-(2-Hydroxyethyl)-7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one

To a solution of methyl2-(7-(hydroxymethyl)-2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-5-oxo-5H-pyrrolo[3,4-b]pyridin-6(7H)-yl)acetate(20.0 mg, 0.04 mmol) in THF (1 mL) was added LiBH₄ (2.39 mg, 0.11 mmol)at 15° C. The reaction was stirred for 15 h before quenching withsaturated aqueous NH₄Cl (0.5 mL), treating with water (10 mL) andextracting the mixture with EtOAc (20 mL×3). The combined organic layerswere dried over anhydrous sodium sulfate, filtered and concentrated. Theresidue was purified by HPLC (ACN/water with 0.1% TFA modifier) toafford the title compound. MS: 429 (M+1). 1H NMR (400 MHz, methanol-d₄):δ 7.87 (1H, d, J=2.8 Hz), 7.74 (1H, s), 7.50 (1H, dd, J=8.8, 2.8 Hz),6.84 (1H, d, J=8.8 Hz), 4.50-4.58 (2H, m), 4.19 (1H, dd, J=7.2, 2.8 Hz),4.06 (1H, dd, J=7.2, 2.8 Hz), 3.75-3.95 (6H, m), 3.53-3.61 (3H, m),3.15-3.21 (2H, m), 2.37 (3H, s), 2.12-2.16 (2H, m), 1.88-1.94 (2H, m).

Assay Protocol

The utility of the compounds as M4 muscarinic receptor allostericmodulators may be demonstrated by methodology known in the art,including by the assay described herein.

CHO-K1 cells stably transfected with human M4 receptor and chimericG-protein Gαqi5 are thawed from liquid N₂ storage, resuspended in growthmedium, plated in black, clear bottom 384 well plates, and incubated16-20 hours at 37° C., 5% CO₂.

On the day of assay, growth medium is removed, the cells are washed 2times with wash buffer, and cells are incuabted in dye loading buffer at37° C., 5% CO₂ for ˜1 h. Following dye loading the cell plates areplaced in a FLIPR Tetra instrument and while monitoring dye fluorescence(excitation 470-495 nM/emission 515-575 nM), 10 uL of test substance atincreasing concentrations is added, and fluorescence values are recordedfor 4 min. Next, 10 uL of acetylcholine is added (final concentrationcalculated so as to achieve 20% of the maximum acetycholine response),and the fluorescence reading is continued for 3.5 min. In some cases, athird addition of acetylcholine (final concentration calculated toachieve 70% of the maximal acetylcholine response) is performed.

The following table shows representative data for the compounds of theExamples as modulators of the M4 muscarinic acetylcholine receptor asdetermined by the assays described herein. Such results are indicativeof the intrinsic activity of the compounds for use as allostericmodulators of the M4 muscarinic acetylcholine receptor.

TABLE 44 Example M4 PAM IP (nM)  1 27  2A 86  2B 734  3 25  3A 637  4 49 4A 2770  5 21  5A 121  6 17  6A 150  7 30  8 14  8A 87  8B 501  9 83 10 179  11 38  12 16  13 174  14 52  15 1990  16 81  17 1166  18 36  1957  20 83  21 50  22 32  23 70  24 167  25 75  26 28  27 43  28A 84  28B1976  29A 63  29B 30000  30 25  31 42  32 37  33 22  34 26  35 24  36302  37 172  38 30  39 1597  40 17  41 11340  42 1732  43A 155  43B 367 44 130  45 53  46 32  47 41  47A 287  48 61  48A 67  49 94  50 657  5151  52 238  53 449  54 8762  55 1121  56 11180  57 61  58 192  59 123 60 207  61 135  62 55  63 145  64 206  64A 192  65 75  65A 164  66 84 67 136  68 79  69 88  70 79  71 42  72 30  73 2247  74 46  75 236  7680  77 214  78 33  79 2277  80 69  81 37  82 121  83 48  84 229  85 2617 86 5690  87 1001  88 381  89 83  90 94  91 60  92 461  93 944  93A 148 94 1734  94A 193  95 616  96 1426  97 800  98 522  99 735 100 1027 101869 102 690 103 138 104 60 105 104 106 298 107 87 108 59 109 20 110 39111 4356 112 20 113 50 114 88 115 119 116 45 117 17 118 141 119 149 120256 121 1919 122 2106 123 144 124 362 125 612 126 216 127 480 128 2374129 1094 130 105 131 1520 132 30 133 611 134 167 135 217 136 3471 137515 138 390 139 106 139A 628 140 4710 141A 82 141B 55 142 270 143A 101143B 117 144 316 145 2163 146 286 147 313 148 31 149 1000 150A 124 150B197 151 32 152 1150 153 528 154 128 155 117 156 1222 157A 93 157B 144158A 452 158B 17 159 28 160 231 160A 627 160B 96 160C 58 160D 37 1611519 161A 21 162 51 162A 59 162B 47 163 277 163A 1135 164 82 164A 202165 467 165A 83 166 90 166A 61 166B 57 167 14 167A 188 168 119 168A 209168B 166 169 183 169A 180 170 40 170A 129 171 79 171A 491 171B 14 172125 172A 905 173 313 173A 207 174 45 174A 22 175 139 175A 3099 176 39176A 264 177 1813 178 2479 178A 18 178B 18 179 168 180 1653 181A 55 181B183 182 3787 182A 473 183 4778 184 246 185A 8632 185B 2529 186 77 187223 187A 295 188 1218 189 265 190 5610 190A 820 191 492 191A 1475 191B30000 192 310 193 1218 193A 312 193B 875 194 532 194A 20 195 68 196 22197 6065 197A 285 198 18 198A 110 199A 60 199B 72 200 96 200A 58 201 230201A 68 202 148 202A 96 203 531 204 1112 205 238 205A 5632 206 589 206A259 207 30 208 329 208A 123 209 2655 210 2583 211 216 212 1832 212A 116213 61 213A 126 214 93 215 304 216 888 216A 288 217 42 218 38 219 25219A 46 220 109 220A 83 221 1078 222 50 223 344 224 3523 225 19 226 136227 435 228 86 229 36 229A 600 230 2117 231 51 232 81 233 394 234A 382234B 78 235 324 236 317 236A 146 237 68 238 49 238A 87 239 36 239A 86240 40 240A 127 241 22 241A 93 242 74 243 73 244 32 244A 28 245 75 246125 247 137 248 88 249 32 250 149 250A 70 251 198 252 94 253 49 254 69255 29 255A 803 256 85 257 84 258 126 259 87 259A 117 260 141 260A 43261 39 262 43 263 57 263A 40 264 36 264A 38 264B 108 264C 40 264D 79264E 125 265 46 265A 100 265B 123 265C 41 265D 65 256E 34 265F 46 266105 266A 44 266B 53 266C 64 266D 43 266E 159 266F 57 266G 69 267 34 267A102 267B 80 267C 109 267D 87 267E 69 267F 17 268 87 268A 169 268B 63268C 53 268D 28 268E 68 268F 39 269 65 270 48 271A 941 271B 38 272 395273A 4500 273B 23 274 1163 275 3966 276 145 277 3403 277A 30000 278 19278A 76 279 30 279A 909 280 438 280A 14 281 23 281A 8063 282 623 282A 38283 44 284 4327 285 8623 286 38 287A 3868 287B 214 288 1793 289 156 290353 291 204 292 174 293 104 294 202 295 137 296 83 297 22 298 24 299 265300 286 301 1145 302 819 303 302 304 1116 305 241 306 320 307 1312 307A279 308 176 309 47 310 101 310A 35 311 686 311A 108 312 651 312A 2512312B 1122 313 30 314 676 315 80 316 198 317 125 318 155 319 96 320 150321 193 321A 434 321B 91 322 499 323A 261 323B 30000 324 17 324A 22 324B28 324C 1143 324D 682 324E 420 325 204 326 1655 327 205 328 61 329A 47329B 241 330 51 331 33 332 368 333 37 334A 67 334B 38 335A 245 335B 259336 182 336A 19 336B 650 336C 33 337A 20 337B 867 337C 42 337D 613 33840 339 13 340 2977 341 23 341A 9 342 3440 342A 884 343 55 343A 27 3441218 344A 760 345 23 346 3076 347 28 348 8173 349 22 349A 22 350 980350A 601 351 40 351A 19 352 2103 352A 239 353 30 354 1465 355 16 356 788357 87 358 8072 359 37 360 1684 361 85 362 1292 363 100 364 3770 365 26366 1237 367 19 368 239613 369 57 370 1189 371 100 372 634 373 69 374A416 374B 45 375 69

While the invention has been described and illustrated with reference tocertain particular embodiments thereof, those skilled in the art willappreciate that various adaptations, changes, modifications,substitutions, deletions, or additions of procedures and protocols maybe made without departing from the spirit and scope of the invention.

What is claimed is:
 1. A compound which is selected from: 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile; 3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin 5-one; 2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; 6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; and 2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 2. The compound of claim 1 which is: 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 3. The compound of claim 1 which is: 3-((1-(3-methyl-5-oxo-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-2-yl)piperidin-4-yl)oxy)benzonitrile; or a pharmaceutically acceptable salt thereof.
 4. The compound of claim 1 which is: 3-methyl-2-(4-((1-methyl-1H-indazol-5-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 5. The compound of claim 1 which is: 3-methyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 6. The compound of claim 1 which is: 3-methyl-2-(4-((5-methylpyridin-3-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 7. The compound of claim 1 which is: 2-(4-(isochroman-7-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 8. The compound of claim 1 which is: 3-methyl-2-(4-((1-methyl-1H-pyrazol-4-yl)oxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 9. The compound of claim 1 which is: 2-[4-(1,3-dihydro-2-benzofuran-5-yloxy)piperidin-1-yl]-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 10. The compound of claim 1 which is: 3-methyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 11. The compound of claim 1 which is: 2-(4-((2,3-dihydrobenzofuran-6-yl)oxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 12. The compound of claim 1 which is: 2-(4-(isochroman-6-yloxy)piperidin-1-yl)-3-methyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 13. The compound of claim 1 which is: 2-(4-((6-methoxypyridin-3-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 14. The compound of claim 1 which is: 3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 15. The compound of claim 1 which is: 6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-phenoxypiperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 16. The compound of claim 1 which is: 6-(2-hydroxyethyl)-3,4-dimethyl-2-(4-((1-methylcyclopropyl)methoxy)piperidin-1-yl)-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 17. The compound of claim 1 which is: 2-(4-((1,3-dihydro-2-benzofuran-5-yl)oxy)piperidin-1-yl)-3,4-dimethyl-6,7-dihydro-5H-pyrrolo[3,4-b]pyridin-5-one; or a pharmaceutically acceptable salt thereof.
 18. A pharmaceutical composition which comprises an inert carrier and a compound of claim 1 or a pharmaceutically acceptable salt thereof.
 19. A method for the treatment of a neurological and/or psychiatric disorder characterized by muscarinic acetylcholine receptor dysfunction comprising the step of administering at least one compound of claim 1, or a pharmaceutically acceptable salt of said compound, to a mammalian patient in need thereof in an amount effective for the treatment of said disorder.
 20. The method of claim 19, wherein the patient has been diagnosed with a need for treatment of the disorder prior to the administering step.
 21. The method of claim 19, wherein the disorder is a neurological and/or psychiatric disorder characterized by mAChR M4 dysfunction.
 22. The method of claim 19, wherein the disorder is a psychotic disorder.
 23. The method of claim 22, wherein the psychotic disorder is selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, postpartum psychosis, psychotic depression, psychotic break, tardive psychosis, myxedematous psychosis, occupational psychosis, menstrual psychosis, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder.
 24. The method of claim 19, wherein the disorder is a cognitive disorder.
 25. The method of claim 24, wherein the cognitive disorder is selected from amnesia, dementia, delirium, amnestic disorder, substance-induced persisting delirium, dementia due to HIV disease, dementia due to Huntington's disease, dementia due to Parkinson's disease, Parkinsonian-ALS demential complex, dementia of the Alzheimer's type, age-related cognitive decline, and mild cognitive impairment.
 26. A method for the treatment of a disorder selected from schizophrenia, brief psychotic disorder, schizophreniform disorder, schizoaffective disorder, delusional disorder, shared psychotic disorder, catastrophic schizophrenia, positive and negative symptoms of schizophrenia, secondary psychotic disorder, bipolar I disorder with psychotic features, and substance-induced psychotic disorder, in a human patient comprising administering a compound of claim 1, or a pharmaceutically acceptable salt of said compound, to the patient in need thereof in an amount effective for the treatment of said disorder.
 27. A method for the treatment of a disorder selected from amnesia, dementia, delirium, amnestic disorder, dementia of the Alzheimer's type, dementia associated with Alzheimer's disease, age-related cognitive decline, and mild cognitive impairment, in a human patient comprising administering a compound of claim 1, or a pharmaceutically acceptable salt of said compound, to the patient in need thereof in an amount effective for the treatment of said disorder. 